CA2961672A1 - Saccharide analogs and agents for the diagnosis and therapy of bacterial infections - Google Patents
Saccharide analogs and agents for the diagnosis and therapy of bacterial infections Download PDFInfo
- Publication number
- CA2961672A1 CA2961672A1 CA2961672A CA2961672A CA2961672A1 CA 2961672 A1 CA2961672 A1 CA 2961672A1 CA 2961672 A CA2961672 A CA 2961672A CA 2961672 A CA2961672 A CA 2961672A CA 2961672 A1 CA2961672 A1 CA 2961672A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- methyl
- halogen
- aryl
- carbocyclyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 208000035143 Bacterial infection Diseases 0.000 title claims description 12
- 208000022362 bacterial infectious disease Diseases 0.000 title claims description 12
- 150000001720 carbohydrates Chemical class 0.000 title abstract description 18
- 238000002560 therapeutic procedure Methods 0.000 title description 4
- 238000003745 diagnosis Methods 0.000 title description 3
- 241000894006 Bacteria Species 0.000 claims abstract description 53
- 239000000700 radioactive tracer Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000003115 biocidal effect Effects 0.000 claims abstract description 19
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 18
- 230000001580 bacterial effect Effects 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 210000002421 cell wall Anatomy 0.000 claims abstract description 5
- -1 nitro, cyano, hydroxy, amino, mercapto, formyl Chemical group 0.000 claims description 528
- 125000000217 alkyl group Chemical group 0.000 claims description 136
- 229910052736 halogen Inorganic materials 0.000 claims description 112
- 150000002367 halogens Chemical class 0.000 claims description 111
- 125000003118 aryl group Chemical group 0.000 claims description 105
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 100
- 125000000623 heterocyclic group Chemical group 0.000 claims description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims description 89
- 239000001257 hydrogen Substances 0.000 claims description 86
- 125000003545 alkoxy group Chemical group 0.000 claims description 78
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 67
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 59
- 125000001589 carboacyl group Chemical group 0.000 claims description 58
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 56
- 125000004414 alkyl thio group Chemical group 0.000 claims description 51
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 48
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000003282 alkyl amino group Chemical group 0.000 claims description 43
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 42
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 28
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 27
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 25
- 125000006239 protecting group Chemical group 0.000 claims description 25
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 24
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 238000003384 imaging method Methods 0.000 claims description 22
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000005647 linker group Chemical group 0.000 claims description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 20
- 239000008103 glucose Substances 0.000 claims description 19
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 19
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 235000000346 sugar Nutrition 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 150000007970 thio esters Chemical class 0.000 claims description 6
- 150000004662 dithiols Chemical class 0.000 claims description 5
- 239000007850 fluorescent dye Substances 0.000 claims description 4
- 230000000704 physical effect Effects 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical group [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-BJUDXGSMSA-N Nitrogen-13 Chemical compound [13N] QJGQUHMNIGDVPM-BJUDXGSMSA-N 0.000 claims description 2
- IGLNJRXAVVLDKE-OIOBTWANSA-N Rubidium-82 Chemical compound [82Rb] IGLNJRXAVVLDKE-OIOBTWANSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 claims description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 2
- CIOAGBVUUVVLOB-VENIDDJXSA-N strontium-82 Chemical compound [82Sr] CIOAGBVUUVVLOB-VENIDDJXSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 12
- 125000001425 triazolyl group Chemical group 0.000 claims 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 230000008685 targeting Effects 0.000 abstract description 7
- 235000002639 sodium chloride Nutrition 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 14
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 229920002774 Maltodextrin Polymers 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000005913 Maltodextrin Substances 0.000 description 11
- 229940035034 maltodextrin Drugs 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 229950009965 radezolid Drugs 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 210000004962 mammalian cell Anatomy 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 229920001282 polysaccharide Polymers 0.000 description 8
- 239000005017 polysaccharide Substances 0.000 description 8
- BTTNOGHPGJANSW-IBGZPJMESA-N radezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(CNCC=3NN=NC=3)=CC=2)C(F)=C1 BTTNOGHPGJANSW-IBGZPJMESA-N 0.000 description 8
- 230000002285 radioactive effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002872 contrast media Substances 0.000 description 7
- 150000004676 glycans Chemical class 0.000 description 7
- 102000016679 alpha-Glucosidases Human genes 0.000 description 6
- 108010028144 alpha-Glucosidases Proteins 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 229960000282 metronidazole Drugs 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 150000003852 triazoles Chemical class 0.000 description 5
- 108010078791 Carrier Proteins Proteins 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 241000224466 Giardia Species 0.000 description 4
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 4
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 description 4
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- AYRXSINWFIIFAE-SCLMCMATSA-N Isomaltose Natural products OC[C@H]1O[C@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)[C@@H](O)[C@@H](O)[C@@H]1O AYRXSINWFIIFAE-SCLMCMATSA-N 0.000 description 3
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- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 3
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
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Abstract
This disclosure relates saccharide analogs such as thiomaltose-based analogs for targeting bacteria and related uses. In certain embodiments, the disclosure relates to methods of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate, wherein the conjugate comprises a thiomaltose-based analog and a molecule of interest under conditions such that the conjugate is transported across the bacterial cell wall. In certain embodiments, the molecule of interest can be a tracer or an antibiotic.
Description
SACCHARIDE ANALOGS AND AGENTS FOR THE DIAGNOSIS AND
THERAPY OF BACTERIAL INFECTIONS
CROSS REFRENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Applications 62/052,545, filed on September 19, 2014, and 62/068,984, filed on October 27, 2014, the contents of which are hereby incorporated in their entirety.
BACKGROUND
The diagnosis and therapy of bacterial infections remains a central challenge in medicine. Infections are currently diagnosed by using blood cultures or tissue biopsy;
however, these methods can only detect late stage infections that are challenging to treat, and also cannot detect bacterial drug resistance. A major limitation preventing the effective treatment of bacterial infection is an inability to image infections in vivo with accuracy and sensitivity. Consequently, bacterial infections can be diagnosed only after they have become systematic or have caused significant anatomical tissue damage, a stage at which they are challenging to treat owing to the high bacterial burden. Although contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo and cannot distinguish infections from other pathologies such as cancer and inflammation. There is a need for the development of contrast agents that can image small numbers of bacteria accurately in vivo.
Bacteria can utilize glycogen, starch, and amylose as carbon sources. Prior to transport through the cell membrane, these polysaccharides are hydrolyzed by the extracellul.ar a-amylase into smaller maltodextrin.s, maltose and isomaltose.
The maltose ABC importer (type I) of Escherichia coli enables the bacteria to feed on maltose and maltodextrins (Bordignon et al., Mol. Microbiol., 2010, 77(6):1354-1366).
Although, maltohexaose contrast agents have been developed to image bacteria, they are hydrolyzed by the serum. amylase. There is a great need for the development of more stable targeting agents that can diagnose and treat the bacterial infections.
Murthy et al. report oligosaccharides conjugates for targeting bacteria. See WO/2012/097223.
Iiind.sgaul reports the preparation of thio galactosi.des as toxin inhibitor bactericides, virucides, and fungicides. US Patent 5,932,554 Zeng et al. report a process for selective removal of sacch.aride th.ioacetyl protective group. CN Patent 103554195.
Gottschaldt et al. report the synthesis of sugar-substituted polypyridine metal complexes and their use as diagnostic, visualization, or therapeutic agents in the treatment of disease. DE Patent 102007032799.
References cited herein are not an admission of prior art.
SUMMARY
This disclosure relates saccharide analogs such as thiomaltose-based analogs for targeting bacteria and related uses. In certain embodiments, the disclosure relates to methods of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate, wherein the conjugate comprises a thiomaltose-based analog and a molecule of interest under conditions such that the conjugate is transported across the bacterial cell wall. In certain embodiments, the molecule of interest can be a tracer or an antibiotic.
In certain embodiments, the disclosure relates to a composition comprising a tracer molecule conjugated to thiol bridging saccharides. In certain embodiments the tracer molecule is a positron-emitting radionuclide. In certain embodiments, the positron-emitting radionuclide is selected from. carbon-1.1, nitrogen-13, oxygen-15, fluorine-18, rubidium-82, and strontium-82. In certain embodiments the tracer is a fluorescent molecule.
In certain embodiments, the fluorescent molecule is a fluorescent dye. In certain embodiments, the thiol bridging saccharide is thiomaltose-perylene.
With regard to any of the conjugates disclosed herein, the saccharides can be a polysaccharide of greater than 2, 3, 4, 5, or 6 sugar oligom.ers bridged by one or more thiol linkages which are typically isolated or substantially purified. In some embodiments, the polysaccharide comprises glucose oligomers, e.g., maltohexaose, a polysaccharide with 6 glucose oligomers. Typically, the glucose oligomers are linked by a thiol bridging alpha 1-44, i.e., 1 to 4, covalent bond. In certain embodiments, the disclosure contemplates thiomaltose-based analog of glucose oligomers and/or 2-deoxyglucose oligomers wherein one or more of the glucose monomers are substituted with a positron-emitting radionuclide In certain embodiments, any of the compounds or saccharide analogs disclosed.
herein or derivatives can be optionally substituted with one or more, the same or different, substituents.
In certain embodiments, the disclosure relates to an antibiotic conjugated to a saccharide analog disclosed herein. In certain embodiments, the antibiotic is selected from
THERAPY OF BACTERIAL INFECTIONS
CROSS REFRENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Applications 62/052,545, filed on September 19, 2014, and 62/068,984, filed on October 27, 2014, the contents of which are hereby incorporated in their entirety.
BACKGROUND
The diagnosis and therapy of bacterial infections remains a central challenge in medicine. Infections are currently diagnosed by using blood cultures or tissue biopsy;
however, these methods can only detect late stage infections that are challenging to treat, and also cannot detect bacterial drug resistance. A major limitation preventing the effective treatment of bacterial infection is an inability to image infections in vivo with accuracy and sensitivity. Consequently, bacterial infections can be diagnosed only after they have become systematic or have caused significant anatomical tissue damage, a stage at which they are challenging to treat owing to the high bacterial burden. Although contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo and cannot distinguish infections from other pathologies such as cancer and inflammation. There is a need for the development of contrast agents that can image small numbers of bacteria accurately in vivo.
Bacteria can utilize glycogen, starch, and amylose as carbon sources. Prior to transport through the cell membrane, these polysaccharides are hydrolyzed by the extracellul.ar a-amylase into smaller maltodextrin.s, maltose and isomaltose.
The maltose ABC importer (type I) of Escherichia coli enables the bacteria to feed on maltose and maltodextrins (Bordignon et al., Mol. Microbiol., 2010, 77(6):1354-1366).
Although, maltohexaose contrast agents have been developed to image bacteria, they are hydrolyzed by the serum. amylase. There is a great need for the development of more stable targeting agents that can diagnose and treat the bacterial infections.
Murthy et al. report oligosaccharides conjugates for targeting bacteria. See WO/2012/097223.
Iiind.sgaul reports the preparation of thio galactosi.des as toxin inhibitor bactericides, virucides, and fungicides. US Patent 5,932,554 Zeng et al. report a process for selective removal of sacch.aride th.ioacetyl protective group. CN Patent 103554195.
Gottschaldt et al. report the synthesis of sugar-substituted polypyridine metal complexes and their use as diagnostic, visualization, or therapeutic agents in the treatment of disease. DE Patent 102007032799.
References cited herein are not an admission of prior art.
SUMMARY
This disclosure relates saccharide analogs such as thiomaltose-based analogs for targeting bacteria and related uses. In certain embodiments, the disclosure relates to methods of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate, wherein the conjugate comprises a thiomaltose-based analog and a molecule of interest under conditions such that the conjugate is transported across the bacterial cell wall. In certain embodiments, the molecule of interest can be a tracer or an antibiotic.
In certain embodiments, the disclosure relates to a composition comprising a tracer molecule conjugated to thiol bridging saccharides. In certain embodiments the tracer molecule is a positron-emitting radionuclide. In certain embodiments, the positron-emitting radionuclide is selected from. carbon-1.1, nitrogen-13, oxygen-15, fluorine-18, rubidium-82, and strontium-82. In certain embodiments the tracer is a fluorescent molecule.
In certain embodiments, the fluorescent molecule is a fluorescent dye. In certain embodiments, the thiol bridging saccharide is thiomaltose-perylene.
With regard to any of the conjugates disclosed herein, the saccharides can be a polysaccharide of greater than 2, 3, 4, 5, or 6 sugar oligom.ers bridged by one or more thiol linkages which are typically isolated or substantially purified. In some embodiments, the polysaccharide comprises glucose oligomers, e.g., maltohexaose, a polysaccharide with 6 glucose oligomers. Typically, the glucose oligomers are linked by a thiol bridging alpha 1-44, i.e., 1 to 4, covalent bond. In certain embodiments, the disclosure contemplates thiomaltose-based analog of glucose oligomers and/or 2-deoxyglucose oligomers wherein one or more of the glucose monomers are substituted with a positron-emitting radionuclide In certain embodiments, any of the compounds or saccharide analogs disclosed.
herein or derivatives can be optionally substituted with one or more, the same or different, substituents.
In certain embodiments, the disclosure relates to an antibiotic conjugated to a saccharide analog disclosed herein. In certain embodiments, the antibiotic is selected from
2 the group comprising sulfonamides, carbapenems, penicillins, diaminopyrimidines, quinolones, beta-lactam. antibiotics, cephalosporins, tetracyclines, notribenzenes, aminoglycosides, macrolide antibiotics, polypeptide antibiotics, nitrofurans, nitroimidazoles, nicotinin acids, polyene antibiotics, imidazoles, glycopeptides, cyclic lipopeptides, glycylcyclines, and oxazolidinones. In certain embodiments, the antibiotic is selected from. dapsone, paraaminosalicyclic, sulfanilamide, sulfamethizole, sulfamethoxazole, sulfapyridine, trimethoprim, pyrimethamine, nalidixic acid, norfloxacin, ciproflaxin, cinoxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin., lomefloxacin, moxifloxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacil.lin, dicloxacillin, flucloxacillin, hetacillin, oxacillin., mezlocilli.n, penicillin G, penicillin V, piperaci.11in, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridin, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedon.e, cefazolin, cefradine, cefroxadin.e, ceftezole, cefaclor, cefonicid, ceforanide, cefprozil, cefttroxime, cefuzonam, cefmetazole, cefoteta, cefoxitin, cefcapene, cefdaloxime, cefdinir, cefditoren., cefetam.et, cefixime, cefmenoxime, cethdizime, cefoperazon.e, cefotaxime, cefotiam, cefpirnizole, cefpiramide, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolen, ceffizoxi.m.e, ceftriaxone, cefoperazone, ceftazidime, cefepime, moxolactam, imipenem, ertapenem, meropenem, aztreonam, oxytetracycline, chlortetracycline, clomocycli.ne, demecl.ocycline, tetracycline, doxycycline, lymecycline, meclocycline, methacycline, rninocycline, rolitetracycline, chloramphenicol, amikacin, gentamicin, framycetin, kanamycin, neomicin, neomycin, netilmi.cin, streptomycin, tobramycin, azithromyci.n, clarithromycin, dirithromycin, erythromycin, roxithromyci.n, telithromycin, polymyxin-B, colistin, bacitracin, tyrothricin, notrifurantoin, furazolidone, metronidazole, tinidazole, isoniazid, pyrazinamide, ethionamide, nystatin, amphotericin-B, hamycin, miconazole, clotrimazole, ketoconazole, fluconazole, tifampacin, lincomycin, clindamycin, spectinomycin, chloramph.enicol, clindamyci.n, col istin, fosfomycin, loracarbef, nitrofurantoin, procain, spectinomycin, tinidazole, ramoplanin, teicoplanin, and vancomycin.
In certain embodiments, the disclosure relates to a method of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate under conditions such that the conjugate is transported across the bacterial cell wall wherein the conjugate comprises a saccharide analog and a molecule of interest.
In certain embodiments, the disclosure relates to an imaging method comprising a) administering a tracer molecule conjugated to a saccharide analog to a subject; and b)
In certain embodiments, the disclosure relates to a method of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate under conditions such that the conjugate is transported across the bacterial cell wall wherein the conjugate comprises a saccharide analog and a molecule of interest.
In certain embodiments, the disclosure relates to an imaging method comprising a) administering a tracer molecule conjugated to a saccharide analog to a subject; and b)
3 scanning the subject for a physical property of the tracer molecule. In certain embodiments the imaging method further comprises the step of detecting the physical property of the tracer molecule and creating an image highlighting the location of the tracer molecule in the subject.
In certain embodiments, the disclosure relates to a method of treating or preventing a bacterial infection comprising administering an effective amount of an isolated conjugate to a subject in need thereof wherein the isolated conjugate comprises an antibiotic and a saccharide analog. In certain embodiments the isolated conjugate is administered in combination with another antibiotic.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates saccharide analogs, e.g., thiomaltose-based analogs designed to image bacterial infections. Left side: illustrates bacteria internalized PET
contrast agent (1) with an I8F derivatized maltodextrin probe (MDP) (1) through the maltodextrin transporter (2). 18F-thiomaltose is designed to image bacteria in vivo by targeting the maltodextrin transport pathway. 18F-thiomaltose is internalized by bacteria. Maltodextrin transporters are not present in mammalian cells and 18F-thiornaltose-based analogs therefore have high specificity for bacteria over mammalian cells. Right side: illustrates imaging bacterial infections in implanted device due to robust accumulation of '8F- M.DPs.
Systemic injection (4) of18F-MDPs can be used to image bacterial implant infections and generate an imaging agent that can diagnose early stage bacterial implant infections at the site of implant (3).
Figure 2 Synthesis of thiomaltose-perylene: a) NaOCH3, Me0H, 55%. b) Tf20, DCM-Pyridine, 63%. c) TEA., DMF, 38%. d) NaOCH3, Me0H, 83%. e) Pyridine, A.c20, 78%. f) NH2NH2.H0Ac, DMF, 81%. g) Trichloroacetonitrile, DBU, DCM, 97%. h) Azidopropanol, TMSOIT, DCM, 63%. i) 1. alkyne-perylene, ('ul, DIPEA, DMF; 2.
Li0H, Me0H, H20, 65% in two steps Figure 3 Synthesis of 18F-thiom.altose: a) 2, Cul, DIPEA, DMF. b) 1. K18F, CH3CN, 110 C; 2. NaOH, H20.
Figure 4 schematically illustrates the retrosynthesis of thionialtose.
Figure 5 schematically illustrates the synthesis of the glucose building block.
Figure 6 schematically illustrates the synthesis of the galactose building block.
Figure 7 schematically illustrates the synthesis of the galactose building block.
Figure 8 schematically illustrates the synthesis of the galactose building block.
In certain embodiments, the disclosure relates to a method of treating or preventing a bacterial infection comprising administering an effective amount of an isolated conjugate to a subject in need thereof wherein the isolated conjugate comprises an antibiotic and a saccharide analog. In certain embodiments the isolated conjugate is administered in combination with another antibiotic.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates saccharide analogs, e.g., thiomaltose-based analogs designed to image bacterial infections. Left side: illustrates bacteria internalized PET
contrast agent (1) with an I8F derivatized maltodextrin probe (MDP) (1) through the maltodextrin transporter (2). 18F-thiomaltose is designed to image bacteria in vivo by targeting the maltodextrin transport pathway. 18F-thiomaltose is internalized by bacteria. Maltodextrin transporters are not present in mammalian cells and 18F-thiornaltose-based analogs therefore have high specificity for bacteria over mammalian cells. Right side: illustrates imaging bacterial infections in implanted device due to robust accumulation of '8F- M.DPs.
Systemic injection (4) of18F-MDPs can be used to image bacterial implant infections and generate an imaging agent that can diagnose early stage bacterial implant infections at the site of implant (3).
Figure 2 Synthesis of thiomaltose-perylene: a) NaOCH3, Me0H, 55%. b) Tf20, DCM-Pyridine, 63%. c) TEA., DMF, 38%. d) NaOCH3, Me0H, 83%. e) Pyridine, A.c20, 78%. f) NH2NH2.H0Ac, DMF, 81%. g) Trichloroacetonitrile, DBU, DCM, 97%. h) Azidopropanol, TMSOIT, DCM, 63%. i) 1. alkyne-perylene, ('ul, DIPEA, DMF; 2.
Li0H, Me0H, H20, 65% in two steps Figure 3 Synthesis of 18F-thiom.altose: a) 2, Cul, DIPEA, DMF. b) 1. K18F, CH3CN, 110 C; 2. NaOH, H20.
Figure 4 schematically illustrates the retrosynthesis of thionialtose.
Figure 5 schematically illustrates the synthesis of the glucose building block.
Figure 6 schematically illustrates the synthesis of the galactose building block.
Figure 7 schematically illustrates the synthesis of the galactose building block.
Figure 8 schematically illustrates the synthesis of the galactose building block.
4 Figure 9 schematically illustrates glycosylation.
Figure 10 schematically illustrates the synthesis of perylene-thiomaltose.
Figure 11 shows uptake of thiomaltose-perylene in Mtb cells. Thiomaltose-perylene (50 1.1M), and uptake was measured using a plate reader (fluorescence intensity at 410/480).
Figure 12 shows a table of uptake of thiomaltose-perylene in Salmonella and pseudomon.as cells.
Figure 13 shows uptake studies in bacterial and mammalian cells. Bacteria (E
coli) and macrophages were incubated with thiomaltose-perylene (20 ilM) for 2 hours.
Cells were washed 3 times with PBS. Cells were lysed using they lysis buffer. The fluorescence intensity from bacteria and mammalian cells was measured by plate reader at 410/480 and the background of lysis buffer was subtracted. The protein content was analyzed by BCA
assay. The uptake of thiomaltose-perylene in bacteria was 98 fold higher than in macrophages.
Figure 14 shows data indicating that thiomaltose is resistant to maltase hydrolysis.
Maltose is hydrolyzed completely in 3 hours, whereas thiomaltose is less than 1%
hydrolyzed.
Figure 15 illustrates certain. embodiments of the disclosure.
Figure 16 illustrates certain embodiments of the disclosure.
Figure 17 illustrates certain embodiments of the disclosure.
Figure 18 illustrates certain embodiments of the disclosure.
Figure 19 shows data indicating that the thiomaltose-radezolid inhibits bacterial growth. E. Coli were grown in a 96 well plate, starting at an O.D. of 0.05.
Thiomaltose radezolid was added to the bacteria, and the bacteria were shaken at 37C
between 1-24 hours. The O.D. of the bacteria was then measured and normalized to untreated bacteria 1050 at 24 hours is approximately 0.5 rnicromolar.
Figure 20 illustrates certain embodiments of the disclosure.
Figure 21 illustrates certain embodiments of the disclosure.
Figure 22 illustrates certain embodiments of the disclosure.
Figure 23 shows data indicating TM-R can effectively kill P. aeruginosa. TM-k and free rad.ezoli.d were incubated with P. aentginosa for 24 hours. 0D600 were used to determine the bacteria growth.
Figure 24 illustrates certain embodiments of the disclosure.
Figure 25 illustrates certain embodiments of the disclosure.
Figure 10 schematically illustrates the synthesis of perylene-thiomaltose.
Figure 11 shows uptake of thiomaltose-perylene in Mtb cells. Thiomaltose-perylene (50 1.1M), and uptake was measured using a plate reader (fluorescence intensity at 410/480).
Figure 12 shows a table of uptake of thiomaltose-perylene in Salmonella and pseudomon.as cells.
Figure 13 shows uptake studies in bacterial and mammalian cells. Bacteria (E
coli) and macrophages were incubated with thiomaltose-perylene (20 ilM) for 2 hours.
Cells were washed 3 times with PBS. Cells were lysed using they lysis buffer. The fluorescence intensity from bacteria and mammalian cells was measured by plate reader at 410/480 and the background of lysis buffer was subtracted. The protein content was analyzed by BCA
assay. The uptake of thiomaltose-perylene in bacteria was 98 fold higher than in macrophages.
Figure 14 shows data indicating that thiomaltose is resistant to maltase hydrolysis.
Maltose is hydrolyzed completely in 3 hours, whereas thiomaltose is less than 1%
hydrolyzed.
Figure 15 illustrates certain. embodiments of the disclosure.
Figure 16 illustrates certain embodiments of the disclosure.
Figure 17 illustrates certain embodiments of the disclosure.
Figure 18 illustrates certain embodiments of the disclosure.
Figure 19 shows data indicating that the thiomaltose-radezolid inhibits bacterial growth. E. Coli were grown in a 96 well plate, starting at an O.D. of 0.05.
Thiomaltose radezolid was added to the bacteria, and the bacteria were shaken at 37C
between 1-24 hours. The O.D. of the bacteria was then measured and normalized to untreated bacteria 1050 at 24 hours is approximately 0.5 rnicromolar.
Figure 20 illustrates certain embodiments of the disclosure.
Figure 21 illustrates certain embodiments of the disclosure.
Figure 22 illustrates certain embodiments of the disclosure.
Figure 23 shows data indicating TM-R can effectively kill P. aeruginosa. TM-k and free rad.ezoli.d were incubated with P. aentginosa for 24 hours. 0D600 were used to determine the bacteria growth.
Figure 24 illustrates certain embodiments of the disclosure.
Figure 25 illustrates certain embodiments of the disclosure.
5
6 PCT/US2015/051262 DETAILED DESCRIPTION
Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled.
to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from. the actual publication dates that can need to be independently confirmed.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.
Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
Targeting Bacteria A central problem in imaging bacterial infections is to develop targeting strategies that can deliver large quantities of imaging probes to bacteria. This has been challenging because typical imaging probes target the bacterial cell wall and cannot access the bacterial intracellular volume. Although numerous contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vi.vo, and cannot distinguish infections from other pathologies such as cancer and inflammation. Within certain embodiments, the disclosure relates to a thiomaltose-based imaging probe which can detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported, and can detect bacteria using a bacteria-specific mechanism. that is independent of host response and secondary pathologies.
In certain embodiments, the thiomaltose-based imaging probe is composed of a fluorescent dye conjugated to a thiomaltose-based analog and is rapidly internalized through the bacteria-specific maltodextrin transport pathway, endowing the thiomaltose-based imaging probes with a unique combination of high sensitivity and specificity for bacteria.
Certain thiomaltose-based imaging probes selectively accumulate within bacteria at millimolar concentrations, and are a thousand-fold more specific for bacteria than mammalian cells. Furthermore, thiomaltose-based imaging probes can image as few as 105 colony-forming units in. vivo and can discriminate between active bacteria and inflammation induced by either lipopolysaccharides or metabolically inactive bacteria.
Contrast agents that are robustly internalized through the bacteria-specific maltodextrin transporter and can image bacterial infections in vivo with improved sensitivity and specificity (see figures 11-14). Thiomaltose-based imaging probes can deliver millimol.ar concentrations of imaging probes into bacteria, making it possible to image low numbers of bacteria. Thiomaltose-based imaging probes also have high specificity for bacteria because mammalian cells do not express the maltodextrin transporter and cannot internalize contrast agents conjugated to thiomaltose-based analogs (figure 13).
Thiomaltose-based imaging probes are typically composed of a (1--44)-thiol linked glucose oligomers. Because thiomaltose-based imaging probes are typically hydrophilic and membrane impermeable, they are efficiently cleared from uninfected tissues in vivo, leading to a low background. Furthermore, the lumen of intestinal tissues or the outer layers of the skin, are not permeable to glucose oligomers. Thiomaltose-based imaging probes delivered systemically should therefore not be internalized by the resident bacterial microflora present in healthy subjects.
Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled.
to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from. the actual publication dates that can need to be independently confirmed.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.
Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
Targeting Bacteria A central problem in imaging bacterial infections is to develop targeting strategies that can deliver large quantities of imaging probes to bacteria. This has been challenging because typical imaging probes target the bacterial cell wall and cannot access the bacterial intracellular volume. Although numerous contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vi.vo, and cannot distinguish infections from other pathologies such as cancer and inflammation. Within certain embodiments, the disclosure relates to a thiomaltose-based imaging probe which can detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported, and can detect bacteria using a bacteria-specific mechanism. that is independent of host response and secondary pathologies.
In certain embodiments, the thiomaltose-based imaging probe is composed of a fluorescent dye conjugated to a thiomaltose-based analog and is rapidly internalized through the bacteria-specific maltodextrin transport pathway, endowing the thiomaltose-based imaging probes with a unique combination of high sensitivity and specificity for bacteria.
Certain thiomaltose-based imaging probes selectively accumulate within bacteria at millimolar concentrations, and are a thousand-fold more specific for bacteria than mammalian cells. Furthermore, thiomaltose-based imaging probes can image as few as 105 colony-forming units in. vivo and can discriminate between active bacteria and inflammation induced by either lipopolysaccharides or metabolically inactive bacteria.
Contrast agents that are robustly internalized through the bacteria-specific maltodextrin transporter and can image bacterial infections in vivo with improved sensitivity and specificity (see figures 11-14). Thiomaltose-based imaging probes can deliver millimol.ar concentrations of imaging probes into bacteria, making it possible to image low numbers of bacteria. Thiomaltose-based imaging probes also have high specificity for bacteria because mammalian cells do not express the maltodextrin transporter and cannot internalize contrast agents conjugated to thiomaltose-based analogs (figure 13).
Thiomaltose-based imaging probes are typically composed of a (1--44)-thiol linked glucose oligomers. Because thiomaltose-based imaging probes are typically hydrophilic and membrane impermeable, they are efficiently cleared from uninfected tissues in vivo, leading to a low background. Furthermore, the lumen of intestinal tissues or the outer layers of the skin, are not permeable to glucose oligomers. Thiomaltose-based imaging probes delivered systemically should therefore not be internalized by the resident bacterial microflora present in healthy subjects.
7 Conjugates, Derivatives, and Related Compounds :In certain embodiments, the disclosure relates to compounds of formula 1, Formula I
or salts thereof wherein.
Q is a polysaccharide comprising a 1 to 4-thiol or oxygen linkage such as thiomaitose;
E is a linking group; and G is a tracer, a drug, an antibiotic, an azide group, or other molecule of interest.
:In certain embodiments, Q is a thiomaltose-based analog comprising glucose, a glucose derivative, and/or a substituted glucose oligomer.
In certain embodiments, E contains a triazole positioned between linking groups such as the following groups alone or in combination, methylene, ethylene, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, beteroaromatic, or saturated or unsaturated hydrocarbon groups.
in certain embodiments, E can be represented by a fbrmula:
_____________ (CR'IR"lX1)m(c R2X2)-(CR'R"Y); __ wherein the symbol represents the point of attachement to Q and G;
in' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'1, R'2 and 1Z."2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X2 and Y is each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NEIS02-, -SO2NI-I-,-(0120420)q-,-(01.2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can. be 1 to 1000;
or salts thereof wherein.
Q is a polysaccharide comprising a 1 to 4-thiol or oxygen linkage such as thiomaitose;
E is a linking group; and G is a tracer, a drug, an antibiotic, an azide group, or other molecule of interest.
:In certain embodiments, Q is a thiomaltose-based analog comprising glucose, a glucose derivative, and/or a substituted glucose oligomer.
In certain embodiments, E contains a triazole positioned between linking groups such as the following groups alone or in combination, methylene, ethylene, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, beteroaromatic, or saturated or unsaturated hydrocarbon groups.
in certain embodiments, E can be represented by a fbrmula:
_____________ (CR'IR"lX1)m(c R2X2)-(CR'R"Y); __ wherein the symbol represents the point of attachement to Q and G;
in' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'1, R'2 and 1Z."2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X2 and Y is each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NEIS02-, -SO2NI-I-,-(0120420)q-,-(01.2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can. be 1 to 1000;
8 r can be Ito 22.
In certain embodiments, E can be connected to Q via the the anom.eric carbon at the reducing end of the polysaccharide In certain embodiments, the disclosure relates to compounds of formula I with Formula IA
¨
R3 o ¨E G
R12 n Formula IA
or salts thereof wherein, A is independently 0 or S at each occurrence;
n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
E is a linking group, for instance as defined above;
G is a molecule of interest such as a radionuclide, fluorescent moiety, an antibiotic, or an azide group;
RI, R2, R3, and R4, are each individually and independently a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, m.ercapto, formyl, carboxy, alkanoyl, carbamoyl, allcoxy, alkylthio, alkylarnino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl., or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (.alky1)2amino, alkylsulfinyl., alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylarnino, ethylarnino, dimethylarnino, diethylarnino, N-methyl-N-ethylarnino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbarnoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfin.yl, mesyl, ethylsulfonyl, m.ethoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
In certain embodiments, E can be connected to Q via the the anom.eric carbon at the reducing end of the polysaccharide In certain embodiments, the disclosure relates to compounds of formula I with Formula IA
¨
R3 o ¨E G
R12 n Formula IA
or salts thereof wherein, A is independently 0 or S at each occurrence;
n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
E is a linking group, for instance as defined above;
G is a molecule of interest such as a radionuclide, fluorescent moiety, an antibiotic, or an azide group;
RI, R2, R3, and R4, are each individually and independently a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, m.ercapto, formyl, carboxy, alkanoyl, carbamoyl, allcoxy, alkylthio, alkylarnino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl., or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (.alky1)2amino, alkylsulfinyl., alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylarnino, ethylarnino, dimethylarnino, diethylarnino, N-methyl-N-ethylarnino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbarnoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfin.yl, mesyl, ethylsulfonyl, m.ethoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
9 N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, A must be S at least once or all of A are S.
In certain embodiments, n is 5 or 6 or more, or n is 3 or 4 or more.
In certain embodiments, R2, R3, and R4 are hydrogen or alkanoyl optionally substituted with R5.
In certain embodiments, Pi is hydrogen, halogen, or hydroxy substituted with a.
protecting group.
In certain embodiments, RI is 18F.
in certain embodiments, E is triazole positioned between linking groups such as the Wowing groups alone or in combination, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.
In certain embodiments, Ci is F.
Certain embodiments include compounds of Formula IA-1:
=.= P = 0 R-0 = . = A =
n' 0. .R1 \ 2 2 1 5R (IA-1), Wherein A is either S or 0, and A' is 0, provided that at least one A. is S.
In certain embodiments, n' 1 or 2, n' is 5 or 6 or more, or n' is 3 or 4 or more.
In certain embodiments, R2, R3, and R4 are hydrogen or alkanoyi optionally substituted with R5.
in certain embodiments, RI .is hydrogen, halogen, or h_ydroxyl, optionally substituted with a protecting group In certain embodiments, R' is '8F.
E is a linker, and in certain embodiments, E can be represented by a formula:
_____________ (CR'l R"1X1):(CR`2R"2X2)-(CR'R"YL __ wherein the symbol represents the point of attachement to A' and G;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'', R"', R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
XI, X2 and Y is each occurrence individually and independently -0-, -S-, -S-S-, -NH-, 4C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -SO2NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted lu.qerocyclyl, or absent;
q can be Ito 1000;
r can be I to 22.
In certain embodiments, E is triazole positioned between linking groups such as the following groups alone or in combination, ether, amine, amide, ester, carbonyl, thioi, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.
In certain embodiments, G is "F.
Certain embodiments include titioglycoside compounds of Formula 1A-2:
= 0 S = = = = = = = 0:.1= = = ...I = 0'E--G
fl I 2 ( IA-2), Wherein R'-R4, n', E and G are as defined above. In certain embodiments, R2, and Ware each hydrogen, and R' is either hydroxyl, hydrogen or halogen, preferably 18F.
In certain embodiments, the disclosure relates to compounds of formula I with formula 1B
R3 0 = TRIR"X)m 0 =
ri = R1.2 Formula 1B
or salts thereof wherein, A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R' and R" are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, -NHS02-, -S02NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be I to 1000;
r can be I to 22;
G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group;
RI, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkyithio, atkylamino, (alkyl)2arni no, alkylsulfinyi, alkylsulfonyi, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkyithio, alkylamino, (alkyOzarnino, alkylsuifinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifiuoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyi, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbarrtoy1, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylearbamoyi, methylthio, ethylthio, methylsulfinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-etitylsulfamoyl, N,N-dimethylsulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamo2,,,,I, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, X or Y is a di-substituted 1,2,3-triazole.
In certain embodiments, the compound of Formula 1B can be represented by the compound of Formula 113-1:
--- = Q 0 A N ,.1 ,, . -(CR R" X ),.õ. (CR2 R"2 X2 )-(CR`R"Y) =
0 Ri '2 R-(LB-1) or salts thereof wherein, A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
A' is 0;
11' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11., 12, 13, or 14;
rri' is 0, 1, 2, 3, 4, 5, 6, 7, 8,9. 10 I, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'1, R"1, R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X' is in each occurence absent;
X2 and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, 4C=0)S-, -SO-, -SO2, NFIS02-, -SO2NE1-,-(CH2C1120)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be I to 1000;
r can be 1 to 22;
G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group;
RI, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2arnino, alkylsulfinyi, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylatni no, (alky1)2arnino, alkykulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, a.cetylamino, Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethytthio, methylsulfinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfanioyl, N,N-diethylsuifamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, In certain embodiments, X2 is a di-substituted 1,2,3-triazote, in other embodiments, Y is absent, and in certain preferred embodiments, .X2 is a di-substituted 1,2,3-triazole and.
Y is absent.
in some embodiments, G can be the following:
U N R
=
. = == 0, 8 R
wherein the symbol $ represents the point of attachement to E;
U is N or CR";
W is N or CR9;
Z is a carbocyclic or heterocyclic ring;
R7 is alkyl., carbocyclyl, or aryl, wheren R7 is optionally substituted with one or more RI-3; or R7 and R11 form_ a heteroca.rbocyclic ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R? is a hydrogen or halogen;
R' is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen; and R'2 is hydrogen;
R13 is in each occurrence independently selected from halogen, nitro, cyano, hydrox.y, trifluoromethoxy, triftuoromethyl, amino, formyl, carbox.y, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyla.mino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, -Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulla.moyl, N,N-diethyl.sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. In certain preferred embodiments, R7 is cyclopmpyl or phenyl, optionally substituted by one or more fluorine atoms.
In certain embodiments, Z can have the formula:
_________________ ,R R131 vvweyw :.,,.,....13 13 13 = N . = = N-1 R R ' )---ic N¨i = . R13 VA1/40,./ R13 R
I '''1/27'w i ,.: =
N ,r R ' = = is . N"--=
I ¨ ==. ..it I = = 11 R fõs = .= N-1 4e'N,µ, N--....,(/ N NH 1=3 R13 ="-- , 4Pe , R
, i ___________________________ NH R
13. .. = -R13 ._._N -----I N¨i 0 õ13 =
/
,R 3 = 13 == 13 = R .
or R R13 wherein the symbol 1 represents the point of attachement to E or or the quinolone fragment and R13 is as defined above. In preferred embodiments, ft" is in each case independently selected from hydrogen, methyl, or ethyl.
I 0 In some embodiments, G can be the following:
R'B R',.) 0 1¨N'it =
= . === ,`---0 Rio wi wherein the symbol i represents the point of attachement to E;
R7 is hydrogen, alkyl, carbocyclyl, or aryl, wheren R7 is optionally substituted with one OF
1 5 more, the same or different V;
R8, R9, Rip, and R" are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkan.oyl, carbamoyl, alkoxy, alkyithio, alkylamino, (alky1)2amino, alkyisulfinyl, alkylsuifonyl, arylsulfortyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, R.10, and R'' are optionally 20 substituted with one or more, the same or different, V;
R1 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mereapto, thrmyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocycly1 optionally substituted with one or more, the same or different, 1113;
R'3 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbarnoyl, rnercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethytamino, dimethytamino, diethytamino, N-methyl-N-ethylamino, acetylamino, -Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylearbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, eth:yrIthio, methylsuifinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-tnethylsulfanioyl, N-ethyisulfamoyl, N,N-dimethyisulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
It certain preferred embodiments, R.1-2 is acetylamitKL
In certain embodiments. G can he:
14; -(C1-12)xl8F, wherein x can be 1, 2, 3, 4, 5, 6, 7 or 8, S/7'33 /mt.
= 4. 4-Issu N = ."%s.1111 µ-:; = Yi¨NO2 = 7 = NH' HOOC
= NH NH . =
. = = 7. 1911 = =
==
or wherein the symbol represents the point of attachment to E.
For embodiments in which G is -(CH2)xl8F, it is preferred that p is 0.
In certain embodiments, the disclosure relates to compounds of formula 1 with formula IC, Vs() 2 1/ 1 6/114 4 8 4 6 PCT/US2015/051262 " ' ................... - E R12 7 tj NI R12 Mr' I 0 _R8 n Formula IC
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
E is a linking group;
Q is N in the ring of Z, or N is an amino or alkylamino group attached to the Z ring;
or Q is 0 of an oxygen attached to the Z ring, wherein the Z ring can be optionally substituted with one or more, the same or different, R13;
U is N or CR.11;
W is N or CR9;
Z is a carbocyclic or heterocyclic ring;
R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfin.yl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl., alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifi.uoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethyl.carbamoyl, N-m.ethyl-Nethylcarbamoyl, m.ethylthio, ethylthio, methylsulfinyl., ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is alkyl, carbocyclyl, or aryl, wheren. R7 is optionally substituted with one or more, the same or different R13; or R7 and Ri 1 form a heterocarboeyetie ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R9 is a hydrogen or halogen;
RIO is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen; and R12 is hydrogen;
R13 is halogen, nitro, cyano, hydroxy, triftuoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, di methytamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylearbamoyl, N-ethylearhamoy1, N,N-dimethylearbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylearbamoyl., methylthio, ethyl thio, methylsuifinyl., ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyi, ethoxycarbonyi, N-methyisulfamoyi, -N-ethyisulfamoyi, N,N-dimethyisulfamoyl, N,N-diethylsulfamo-yl, N-methyl-N-eth2,,,,Isulfamoyi, earboeyelyl, ary I, or heterocyclyl.
In certain embodiments, E is -(01.'R"X)m-(CR'R"Y)p- wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, lit, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R' and R" are at each occurrence individually and independently hydrogen, alkyl., halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-, -NH(C=0)-, (C=0)NEI- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -SO2N1-1-, -(C1-12CH20)q-, -(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disUbstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula !ID, R3 = 'CRR"X)m -(CFM"Y)p R7 j R12 (-) R1 L N U N
TR12 .'I 0 R8 Formula ID
or salts thereof wherein, U is N or CR11;
W is N or CR9;
A. is 0 or S at each occurrence provided A must be S at least once or all of A
are 51;
n is 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15;
rn. is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21., 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21., 22, or 23;
R.' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH--(0=0)-, -NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, NitS02-, -SO2NH-, 4CH2CF120)tr, -(0-12)r-, a disubstituted carhocycY., a di-substituted aryl, a disubstituted heterocyclyl, or absent;
ean be 1 to 1000;
r can be 1 to 22;
R1., R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyan , hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylarnino, (alky1)2amino, aikyisuifinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkyiamino, (alky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyt, amino, thrmyl, carboxy, carbamoyl, mercapto, sulfamoyl, 'methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylaini no, Nmethylearbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-methylthio, ethyithio, methylsultinyl, ethylsulfinyi, mesyl, ethylsulfbnyl, methoxycarbonyi, ethoxycarbonyi, N-methylsuifamoyl, N-ethylsulfamoyl, N,N-dimethylsuifamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylstilfamoyi, carbocyclyl, aryl, or heterocyclyl;
R7 is alkyl, carbocycl.2,,,,I, or aryl, wheren R7 is optionally substituted with one or more, the same or different R13; or R7 and R1 I form a heterocarbocyclic ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R9 is a hydrogen or halogen;
RIO is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen; and R12 is hydrogen;
R13 is halogen, nitro, cyano, hydroxy, tTifitioromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, niethylamino, ethytarnino, dimethylamino, diethytarnino, N-methyl-N-ethylamino, acetylamino, Nmeth.2,,,,Icarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-tnethyl-Nethylcarbamoyi, methylthio, ethylthio, methylsulfinyl., ethylsulfinyl, mesyl, ethylsuifonyl, meth.oxycarbonyl, ethoxycarbonyl, N-methyisulfamoyl, N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, the disclosure relates to compounds of formula I with formula = === A E ¨1\1 = = 111011 R
µ1\111N R- == = = = =
= = ilk 9 0 0 =ft.
1 fl = 1,/,-k Rio = = = im Lcss,R12 Formula IF
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15;
A is 0 or S at each occurrence provided A 'must be S at least once or all of A
are S;
E is a linking group; for example, of tbimula In certain embodiments, E can be 'represented by a formula:
_____________ (CR'1R"1 X1 ),(CRR"2X2)-(CR'R"Y),..) wherein the symbol represents the point of attachement to A and the triazoie m' is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R"1, R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
V is each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (CO)NH- -0(C-0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, -NHS02-, -SO2NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
X2 and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, 4C=0)S-, -SO-, -SO2, NFIS02-, -SO2NE1-,-(CH2C1120)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be 1 to 1000;
r can be 1 to 22;
R1, R2, R3, and R4, are each individually and independently hydrogen, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, aikyisuifinyl, alkylsulfortyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 arc optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, aLkylthio, alkyiamino, (alky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trilluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethytarnino, dimethyla.rnino, diethytarnino. N-methyl.-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethyl.carbamoyl, methylthio, ethylthio, m.ethylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is hydrogen, alkyl, carbocyclyl, or aryl, wheren R7 is optionally substituted with one or more, the sam.e or different R13;
R8, R9, R10, and R11 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl., carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfin.yl, alkylsulfonyl, arylsul.fonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, RIO, and R11 are optionally substituted with one or more, the same or different, R13;
R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl., carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, allcylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, su.lfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylarnino, dimethylarnino, diethylarnino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethyl.carbamoyl, N-methyl-N-ethylcarbamoyl., m.ethylthi.o, ethylthio, methyl.sulfi.nyl., ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, E is -(CR'R"X)m-(CR'R"Y)t, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
In certain embodiments, E is -(CH2)m- wherein m. is is I, 2, or 3.
R' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-, -NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, NHS02-, -S02NH-, -(CH2CH2O)q, -(CH2),-, a disubstituted carbocyclyl, a di-substituted.
aryl, a disubstituted h.cterocyclyl, or absent;
q can be Ito 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula. 1G.
N
.=
n Formula IC
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8, 9, .10, 11, 12, 13, 14, or 15;
A. is 0 or S at each occurrence provided A must be S at least once or all of .A are S;
E is a linking group; for example a formula:
_____________ (CR'l R"1X1 )(CR'2R"2X2)-(CR'R"Y), wherein the symbol represents the point of attachment to A and triazole;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3,4. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R"', It'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X1 is each occurrence individually and independently -0-, -S-, -S-S-, -(C-0)-, -NEI(C=0)-, (C=0)NII- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(0=0)S-, -SO-, -S02, -NEIS02-, -SO2NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
X2 and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (0=0)MT.- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, NIIS02-, -SO2NE1-,-(CH2C1120)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyelyl, or absent;
q can be Ito 1000;
r can be 1 to 22;
G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest;
RI., R2, R3, and R4, are each individually and independently -(C=0)0CH2(C=0)alkyl, -0(C=0)0CH2(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, form.yl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyD2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R.1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylarnino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, aryl.sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R.6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylarnino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is -(C=0)0CH20(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, form.yl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;
R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyD2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl., carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R14;
R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluorom.ethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfln.yl, mesyl, ethylsulfonyl, m.ethoxycarbonyl, ethoxycarbonyl, N-meth.ylsulfamoyl, N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-eth ylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, E is -(CR'R"X)m-(CR'R"Y)p- wherein iS I, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 74;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
In certain embodiments, E is -(CH2)m- wherein m is is 1, 2, or 3.
R' and R." are at each occurrence individually and independently hydrogen, alkyl., halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-, -N1-1(C=0)-, (C=0)NI-1- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -SO2NH-, -(CH2CH20)q-, -(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl., a disubstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula o R--0 = 0= == A E-N 1101 =
== = = = == = C S. = 110 Rio = = = = === = = = N
R2 0 ' =
Formula HI
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
E is a linking group;
R1, R2, R3, and R4, are each individually and independently independently--(C=0)0CH2(C=0)alkyi , -0(C=0)0CH2(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mereapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkyisulfinyl, alkylsuifortyl, arylsulfonyl, earbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the sam.e or different, R.6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethyl.carbamoyl, methylthio, ethylthio, m.ethylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;
R8, R.9, RIO, and R11 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyl.sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, RIO, and 111 I are optionally substituted with one or more, the same or different, R13;
R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;
R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl., carbocyclyl, atyl, or heterocyclyl optionally substituted with one or more, the same or different, R14;
R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylearbamoyl, N,N-diethylcarbamoyi, N-methyl-N-ethylcarbamoyl, methyltbio, ethytthio, methylsuifinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxyearbonyl, ethoxyearbonyi, N-methyisulfamoyi, N-ethy N,N-ditnethy N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
in certain embodiments, E is -(CR'R."X)m-(CR'R"Y)p- wherein m. is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
in certain embodiments, E is -(C11.2)m- wherein m is is 1, 2, or 3.
R' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH- , -(C=0)-, -NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - -SO2N11-, 40-120-120)q-, -(CIE12)r-, a &substituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can. be 1 to 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of fbrmula I with __ fot mula 1K, R4, = 8 R2 0[CH2jm-N
µ1\15-. N 11Z = = = = = 0 R10 = =1111r = N
Formula 1K
or salts thereof wherein, M is 2, 3, or 4;
R1, R2, R3, and R4, are each individually and independently -0(C=0)0CH20(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mereapto, fonnyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyistilfonyl, arykulfonyl, carbocyclyl, aryl, or heterocyelyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the sam.e or different, R.6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethyl.carbamoyl, methylthio, ethylthio, m.ethylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, R7 is ---(C=0)0CH20(C=0)a1kyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;
R8, R.9, RIO, and RI I are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyl.sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, RIO, and Ri I are optionally substituted with one or more, the same or different, R13;
R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;
R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl., carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R14;
R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyi, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsuifinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyi, N-methyisulfamoyi, N-ethylsulfamoyi, N,N-ditneth.yisulfamoyi, N,N-diethylsulfamoyi, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, in certain embodiments, the disclosure relates to compounds of fbrmula I with fotmula IL, o ***, 0 N
R3-0 = I.== A -E-N
0 =
F! = 1 n 02 Formula IL
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15;
A. is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
E is a linking group; for example a formula:
__________________________________________ (CR'1 R"1 X1)(CR'2R"2x2)---(CR'R"Y);
N;vherein the symbol represents the point of attachem.ent to A and imidazole;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
WI, R'2 and 1Z."2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X' is each occurrence individually and independently -0-, -S-, -S-S-, _(CO)_, -NH(C=0)-, (C=0)NH-, -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, -NEIS02-, -SO2NH-, -(CH2CH20)(4-,-(Cli2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
X2 and Y are at each. occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -S02NH-, -(CH2CH20)q-, -(Cf12),, a disubstituted carbocyclyl, a di-substituted aryl, a &substituted heterocyclyl, or absent;
q can be 1 to 1000;
r can be Ito 22;;
R1, R2, R3, and R.4, are each individually and independently -(C=0)0CH20(C=0)alkyl, -0(C=0)0CH20(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, form.yl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyD2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R.1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylarnino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, aryl.sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylarnino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylarnino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, meth.oxycarbonyl, eth.oxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, E is -(CR'R"X)in-(CR'R"Y)p- wherein m is 1., 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 1.5, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
In certain embodiments, E is -(CH2)m- wherein m is is I, 2, or 3.
R' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C...0)-, -NFI(C=0)-, (C...0)NH-, -0(0=0)-, -(C=0)0-, -S(C:=0)-, -(C....0)S-, -SO-, -S02, - NHS02-, -SO2NH-, -(CH2CH20)q-, -(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be Ito 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula IK, R=,-) = = =====
== = 1 S = = = = 0 R2 = =.'= 0[CH2.]ril-N
Formula 1K
or salts thereof wherein, al is 2, 3, or 4;
RI, R2, R3, and R4, are each individually and independently ---0(C=0)0C1-120(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, atkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyisulfonyi, arylsultbnyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, rhercapto, formyl, carboxy, earbamoyl, alkoxy, alkylthio, alkyiamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, thrmyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, etboxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylatni no, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbanioyl, methylthio, ethyithio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-tnethylsulfamoyl, N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsuifamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, awl, or heterocyclyl.
In certain embodiments, the disclosure relates to a composition comprising a compound of formula if:
= = 0 Formula II
or derivatives thereof wherein, A is 0, NH, S or a direct bond to R8;
RI., R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen, hydroxy, mercapto, halogen, amino, alkyl, alkoxy, tracer, 18F optionally substituted with a protecting group or optionally substituted with one or more, the same or different, R9;
R8 is E-G, wherein E is a linking group; G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest; or R8 is a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkyl.amino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R9;
R9 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R1.0 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, allcylarnino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R1.1 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylami.no, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R.12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylami.no, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the sam.e or different, R.13; and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylarnino, dimethylarnino, diethylamino, N-methyl-N-ethylarnino, acetylarnino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-inethylsulfamoyl, N-ethylsulfamoyl, N,N-dimetitylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, earbocyclyi, aryl, or heteroeyelyi.
In certain embodiments, R1, R2, R3, R4, R5, R6, and R7 are, the same or different -0(C=0)0CH20(C=0)alkyl, hydrogen, hydroxy, mercapto, halogen, amino, alkyl, alkoxy, tracer, '8F optionally substituted with a protecting group or optionally substituted with one or more, the same or different, R9.
In certain embodiments, the disclosure relates to compounds of formula II with formula HA, =
=
Formula IIA
or derivatives thereof wherein, A is 0, NH, S or a direct bond to R8;
RI, R2, R.3, R4, R5, R6, and R7 are, the same or different, hydrogen or a protecting group;
R8 is E-G, wherein E is a linking group; (ii is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest; or R8 is a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyisulfonyi, arylsultbnyl, carboeyelyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R9;
R9 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkytamino, (a1ky1)2atnino, alkylsulfonyl, aryisuifonyl, carbocyciyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
RIO is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (a.lky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein RIO
is optionally substituted with one or more, the same or different, R.11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylami.no, (alkyl)zamino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the sam.e or different, R.12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthi.o, alkylami.no, (alkyl.)2amino, alkylsu.lfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the sam.e or different, R.13; and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluorom.ethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylarnino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsu.lfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
R1, R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen or -(C...0)0CI-12(0=0)alkyl.
Pharmaceutical Formulations Within certain embodiments, the disclosure contemplates compounds and conjugates disclosed herein in pharmaceutical composition, optionally as a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable excipient. Pharmaceutical compositions of the compounds of this application, or derivatives thereof, can be formulated as solutions or lyophilized powders for parenteral administration. Powders can be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic aqueous solution. Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral administration but can also be used for oral administration. Excipients, such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate, can also be added.
Alternatively, these compounds can be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols or water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier can also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation can be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. Such a liquid formulation can be administered directly p.o. or filled into a soft gelatin capsule.
The pharmaceutical compositions of the application can be in the form of a sterile injectable preparation. Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
In some cases, protective groups can be introduced and finally removed.
Certain "protective groups" such as an N-acetyl group, can be incotporated and remain as part of the desired compound. Suitable protective groups for amino, hydroxy and carboxy groups are described in Greene et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991. Standard organic chemical reactions can be achieved by using a number of different reagents, for examples, as described in Larock:
Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
Radio-labeling a small molecule, such as a compound of the present application, usually involves displacement of a suitably activated precursor with a radioactive moiety in a compatible reaction media. In the case of 18F-labeling, the [18F]fluoride attachment to the precursor occurs via n.ucleophilic substitution of a leaving group, such as mesylate, tosylate, bromide, iodide or diazonium salt, or nitro group. Depending on the compound, the preparation of a radio-labeled compound generally consists of at least two steps. The first step involves the preparation of radiol.abeling precursor, in which various functional groups have been appropriately protected and a proper leaving group has been incorporated. The second sequence then involves the radio-labeling, and removal of the protecting group as known in the art Terms As used herein, "alkyl" means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from. 1 to 10 carbon atoms, while the term "lower alkyl" or "Cl- 4 alkyl" has the same meaning as alkyl but contains from 1 to 4 carbon atoms. The term "higher alkyl" has the sam.e meaning as alkyl but contains from 7 to 20 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n hexyl, n-septyl, n-octyl, n-nonyl., and the like;
while saturated branched al.kyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2- butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl.-2-butenyl., 2,3-dimeth.y1-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- methyl-l-butynyl, and the like.
Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles"
or "carbocycl.y1" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.
"Heterocarbocycles" or heterocarbocycly1" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which can be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatorns can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. Heterocarbocycl.es include morpholinyl, pyrrol.idinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofmnyl, tetrahydropyranyl., tetrahydropyrid.inyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
"Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems can, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.
As used herein, "heteroaryl" refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems can, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl., isooxazolyl, benzoxazolyl, pyrazolyl, irnidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl"
includes N-alkylated derivatives such as a 1-methylimidazol-5-ylsubstituent.
As used herein, "heterocycle" or "heterocycly1" refers to mono- and polycycl.ic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. The mono- and polycycli.c ring systems can be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycl.es, heteroaryls, and the like.
"Allcylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., -S-C113).
"Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n.-propoxy, propoxy, n-butoxy, s-butoxy, t-butoxy.
"Alkylamino" refers an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH3).
"Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bride (i.e., -(C=0)alkyl).
"Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., -S(=0)2alkyl) such as mesyl and the like, and "Arylsulfonyl"
refers to an aryl attached through a sulfonyl bridge (i.e., - S(=0)2a1y1).
"Allcylsulfinyl" refers to an alkyl as defined above attached through a sulfinyl bridge (i.e. -S(=0)alkyl.).
The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents."
The molecule can be multiply substituted. In the case of an oxo substi.tuent ("=0"), two hydrogen atoms are replaced. Example substituents within this context can include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=0)Rb, -NRaC(=0)NRaNRb, -NRaC(=0)0Rb, NRaSO2Rb, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRb, -0C(=0)NRaRb, -0Ra, -SRa, -SORa, S(=0)2Ra, -0S(=0)2Ra and -S(=0)20Ra. Ra and Rb in this context can be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
The term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.
As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
As used herein, the term "combination with" when used to describe administration with an additional treatment means that the agent can be administered prior to, together with, or after the additional treatment, or a combination thereof.
As used herein, "salts" refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylarnines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. In preferred embodiment the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
"Subject" refers any animal, preferably a human patient, livestock, rodent, monkey or domestic pet.
As used herein, the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analog. The derivative can be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen and hydrogen or replacing an amino group with a hydroxyl group or vice versa. The derivative can be a prodrug. Derivatives can be prepare by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry text books, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.
As used herein, the term "saccharide" refers to sugars or sugar derivatives, polyhydroxylated aldehydes and ketones, e.g., with an empirical formula that approximates Cm(H20)n, i.e., wherein m and n are the same or about the same. Contemplated saccharides include, e.g., maltose, isomaltose, and lactose with an. empirical formula of Cl2H22011. The term is intended to encompass sugar monomers, oligomers, and polymers. The terms oligosaccharide and pol.ysaccharide are used interchangeably, and these saccharides typically contain between two and ten monosaccharide units, or greater than ten monosaccharid.e units. In certain embodiments of the disclosure, the saccharide is a dextrin, maltodextrin, or cyclodextrin. Dextrins are mixtures of polymers of D-glucose units linked by a-(1¨>4) or a-(1¨>6) glycosidic bonds. Maltodextrin consists of D-glucose units connected in chains of variable length. The glucose units are primarily linked with a(I ¨>4) glycosidic bonds. Maltodextrin is typically composed of a mixture of chains that vary from three to nineteen glucose units long. Maltose is a disaccharide formed from two units of glucose joined with an a(1¨>4)bond. Isomaltose has two glucose molecules linked through an. a(1¨>6) bond. In certain. embodiments, the disclosure contemplates cyclic and non-cyclic polysaccharides. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, such as alpha cyclodextrin; a six membered sugar ring molecule; beta cyclodextrin, a seven sugar ring molecule; and gamma cyclodextrin, an eight sugar ring molecule.
The term "thiomal.tose" and "thiomaltose" analogs refers to maltose, saccharides, or polysaccharides, wherein one or more to the sugar units are connect by a bridging thiol. In certain embodiments, the sugar units are glucose bridged by thiol through a 1-4 and or 1¨+6 bond.
As used herein, the term "conjugate" or "conjugated," and the like refer to molecular entities being linked together through covalent bonds. Conjugation can be accomplished by directly coupling the two molecular entities, e.g., creating an ester or amide from a hydroxyl group, amino group, and a carboxylic acid. Conjugation can be accomplished by indirectly coupling the two molecular entities, e.g., instituting a linking group such as a polyethylene glycol. Conjugation can be accomplished by modifying the molecular entities with chemical groups that react with one another, e.g., allcyne-functionalized entity with an azide-functionalized entity or the reduction of thiol groups on individual entities to form a disulfide bond.
"Positron emission tomography (PET) refers to an imaging technique that produces a three-dimensional image by detecting pairs of gamma rays emitted indirectly by a positron-emitting radionuclide tracer. Three-dimensional images of tracer concentration within the area are then constructed by computer analysis. A. radioactive tracer is administered to a subject e.g., into blood circulation. Typically there is a waiting period while tracer becomes concentrated in areas of interest; then the subject is placed in the imaging scanner. As the radioisotope undergoes positron emission decay, it emits a positron, an antiparticle of the electron with opposite charge, until it decelerates to a point where it can interact with an electron, producing a pair of (gamma) photons moving in approximately opposite directions. These are detected in the scanning device.
The technique typically utilizes simultaneous or coincident detection of the pair of photons moving in approximately opposite direction (the scanner typically has a built-in slight direction-error tolerance). Photons that do not arrive in pairs (i.e. within a timing-window) are typically ignored. One typically localizes the source of the photons along a straight line of coincidence (also called the line of response, or LOR). This data is used to generate an image.
The term "radionuclide" or "radioactive isotope" refers to isotopes exhibiting radioactive decay (i.e., emitting positrons) and radiolabeling agents comprising a radioactive isotope (e.g., [11C]methane, [11C]carbon monoxide, [11C]carbon dioxide, r11 Ciphosgene, [11C]urea, [11C]cyanogen bromide, as well as various acid chlorides, carboxylic acids, alcohols, aldehydes and ketones containing carbon-11). Such isotopes are also referred to in the art as radioisotopes or radionuclides. Radioactive isotopes are named herein using various commonly used combinations of the name or symbol of the element and its mass number (e.g., 18F, F-18, or fluorine-18). Exemplary radioactive isotopes include 1-124, F-18 fluoride, C-11, N-13, and 0-15, which have half-lives of 4.2 days, 110 minutes, 20 minutes, 10 minutes and 2 minutes, respectively. The radioactive isotope is preferably dissolved in an organic solvent, such as a polar aprotic solvent.
Preferably, the radioactive isotopes used in the present method include F-18, C-11, 1-123, 1-124, 1-127, 1-131, Br-76, Cu-64, Tc-99m, Y-90, Ga-67, Cr-51, Ir-192, Mo-99, Sm-153 and II-201. Other radioactive isotopes that can be employed include: As-72, As-74, Br-75, Co-55, Cu-61, Cu-67, Ga-68, Ge-68, 1-125, 1-132, In-111, Mn-52, Pb-203 and Ru-97.
Other methods of preparing radiolabeled ligands are well known in the art.
Example of such methods are disclosed in, for example: 1) Jewett, D. M. (1992) A
Simple Synthesis of[IC]Methyl Triflate Appl. Radiat. Isot. 43, 1383-1385; 2) Crouzel, C.
Langstrom, B., Pike, V. W., and Coenen, H. H. (1987) Recommendations for a practical production of [ 1C]methyl iodide Appl. Radiat. Isot. Int. J. Appl. Instrum. Part A 38, 601-603; Dannals, R.
F., Raven, H. T.; 3) Wilson, A. A. (1990) Radiochemistry of Tracers for Neurotransmitter Receptor Studies. In: Quantitative Imaging: Neuroreceptors, Neurotransmitters, and Enzymes. (Edited by Frost), J. J. Wagner Jr., H. N. pp. 19-35, Raven Press, New York; 4) Jewett, D. M., Manger, T. J., and Watkins, G. L. (1991) Captive Solvent Methods for Fast Simple Carbon-11 Radioalkylations. In: New Trends in Radiopharrnaceutical Synthesis, Quality Assurance and Regulatory Control (Edited by Emran, A. M.) pp. 387-391.
Plenum Press, New York; 5) Marazano, C., Maziere, M., Berger, G., and Comar, D.
(1977) Synthesis of methyl iodide-11C and formaldehyde-11C. Appl. Radiat. Isot.
28, 49-52;
6) Watkins, G., Jewett, D., Mulholland, G., Kitboum, M., and Toorongian, S.
(1988) A
Captive Solvent Method for Rapid N-[ 1C]Methylation of Secondary Amides Application to the Benzodiazepine, 4'-Chlorodiazepam (R05-4864) Appl. Radiat. Isot. 39, 441-444; and 7) Wilson, A. A., DaSilva, J. N., and Houle, S. (1996) In vivo evaluation of [
IC] and ['5F]-labeled cocaine analogs as potential dopamine transporter ligands for positron emission tomography Nucl. Med. Biol. 23, 141-146. The subject matter of all references cited herein are incorporated herein by reference in their entirety.
As used herein, a "linker" refers to any molecular configuration that joins molecular moieties. It includes molecules with covalent and non-covalent interactions. A
prefer linker is a polymer, i.e., molecule with repeated linking moieties. The linked moieties can be identical in structure or vary, e.g., copolymers. Linking polymers include, but are not limited to, biological polymers, polyethylene glycols, hydrocarbon chains, alkylacrylates, alkylacrylamides, amides, esters, polypeptides, and derivatives thereof A "protecting group" refers to those moieties that are introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction or to facilitate purification. Protecting groups can be categorized by the reaction conditions and/or reagents that are used to remove them such as acid labile protecting groups, base labile protecting groups and hydrogenation removable protecting groups. For example, acid labile protecting groups, such as tBu or Boc, typically decompose when exposed to strong acidic conditions providing a hydrogen substituent in place of tBu or Boc protecting group. .Acetyi esters and thioesters of alcohols and thiols are examples of base labile protecting groups. Additional examples of protecting groups include, but are not limited to, 4-methoxy-2,3,6-trimethylphenypsullonyl (Mtr), 2,2,5,7,8-pentamethyl-chroman-6-sulphonyl (Pm.c), tosyl (Tos), mesitylenesulfonyi (Mts), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyi (Tmob), tripheylmethyi (Trt), 9-fiuorenytmethyloxycarbortyl (fmoc), tert-butyl (tBu), benzyl (Bzi), t-butoxymethyl ether (Bum), (2,4-dinitrophenol) Dnp, benzyloxymethy1 (Born), benzyloxycarbonyl (Z), 2-chloro--benzyloxycarbonyl (CAZ), t-butyloxycarbonyl (Boc), form.yi (CHO) or 2-bromobenzyloxycarbonyl (BrZ) and heterocycles such as succinimide, maleimide, and 'ph.athalimide. Protecting groups can be in the form of derivatives, e.g., having one or more substituents.
EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and therapeutic methods of the disclosure, and are not intended to limit the scope of what the claimed embodiments.
Synthesis of thiomaltose-perylene In order to test the specificity of thiomaltose for bacteria, a thiomaltose derivative labeled with the fluorescent dye was synthesized., perylene (15), using an a.zido-thiomaltose (14) as the synthetic intermediate. The procedure used for the synthesis of thiomaltose-'perylene (15) is shown in Figure 2. .Azido-thiornaltose (14) was first synthesized by lewis acid promoted glycosylation between the thiomaltose imidate donor (13) and a.zidopropanol. Thiomaltose-perylene was then synthesized by conjugating the perylene dye onto azidothiomaltose (14) via the click reaction, followed by deprotection of the acetyl protecting groups using lithium hydroxide. Synthetic details for the synthesis of thiomaltose (10), azidothiomaitose (14) and thiomaltose-perylene (15) are provided.
Synthesis of thiomaltose (10) To a stirred solution of a-D-glucopyranose, 4-S-(2,3,4,6-tetra-0-acety1-13-D-glucopyranosyl)-4-thio-1,2,3,6-tetrabenzoate 9 (,0 g, 10 rnmol) in anhydrous CH3OH (15 nit) was added NaOCH3 (100 mg, 20 mmol) under an atmosphere of N2 at room temperature, and the reaction was stirred at room temperature for 12 hours.
The reaction mixture was neutralized by adding acidic DOWEX resins, filtered, and concentrated in vacuo. The resulting residue was re-dissolved in DIVIF (10 mL), and precipitated by adding ether (100 mL). The precipitated powder was collected and dried in vacuo to afford the product 10 (300 mg, 83%) (a and 13 mixture). '1-1 NMR (D20, 400 MHz): 6 (ppm) 5.01 (d, 3./(H,H) = 10,2 Hz, 0.6H), 4.82 (d, 3./(H,H) = 4,8 Hz, 1H), 4.33 (d, 3./
(F1,11) = 3.6 Hz, 0.4H), 3.71-3.74 (m, 2H), 3.67-3.63 (m, 3H), 3.5-3.49 (m, 2H), 3.43 (dd. 3./(1-1,H) = 10.2 Hz, 1H), 3.26-3.21 (m., 311), 3.0-2.98 (m, 1H), 2.83-2.85 (in, 11-1). 13C NMR
(1)20, 100 MHz): 8 (ppm) 95.8, 91.5, 85.2, 85.1, 85.1, 81.2, 80.0, 79.6, 78.5, 77.9, 77.8, 77.0, 76.8, 75.8, 74.3, 74.1, 73.7, 73.1, 70.8, 62.8, 62.7, 62.2, 61.5, 48.1, 47.5. MS
(MALDI) m/z Found: 381.79, calculated: C12H22010SNa [M+Na ] 381.08.
Synthesis of azidothiomaltose (14) To a stirred solution of thiamaitose imidate 13 (0.16 g, 0.2 tranol) and 3-azidopropanol (0.1 g, 1,0 mmol) in dry DCM (5 nit) was added 4A M.S. The mixture was stirred under nitrogen at 0 "C for 1 hour. TMSOTf (45 4, 0.20 mmol) was then added and the mixture was stirred at 0 "C for 2 hour, The reaction was quenched with Et3N and.
concentrated in vacuo. The residue was dissolved in Et0Ac (20 rnL) and washed with water (5 ml, x 2) and brine (10 mt), The organic phase was dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue was purified by flash column chromatography on silica gel (h.exane/Et0A.c, 1:1) to afford 14 (92.6 mg, 63%). '11. NMR (400 Pv1Hz, CDC13): 6 (ppm) 5.89 (d, 1 H, J = 5.8 Hz, 1-H (a thiol linkage)), 5.28-5.21 (m, 2H), 5.06 (1H, m), 4.95 (111, m), 4.78 (1H, m), 4.65 (1H, in), 4,46 (1H, d,J= 8.6 Hz, 1.-H (13)), 4.33 (1H, m), 4.25-4.20 (2H, m), 4.11 (1H, m), 3.89 (1H, in), 3.58-3.63 (2H, m), 3.35 (2H, t, J=
6.0 Hz, CH2), 2.97 (2H, t, J= 6.0 Hz, CH2), 2.12-1.99 (s, 21 1-1, CH3), 1.83 (2H, m, CH2).
13CNMR. (100 MHz, CDCI.3): 6 (ppm) 170,5, 170,4, 170.2, 169.9, 169.8, 169.5, 169.4, 100.3, 82.4, 76.7, 75.7, 72.7, 72.5, 70.3, 70.1, 69.7, 68.6, 67.9, 66.3, 63.6, 61.5, 47.9, 43.7, 28.9, 20.8, 20.7, 20.6, 20.6, 20.5, 20.4. HRMS (MALDI) m/z Found: 758.2089, calculated:
758.2054 for C29H4iN3017SNa [M+Na]-F.
Synthesis of thiomaltose-perylene (15) To a stirred solution of 14 (15.0 mg, 0.02 mmol) and alkyne functionalized perylene dye (13.0 mg, 0.04 mmol) in DM? (5 mL) was added Cul (0.2 mg, 1.0 iumol) and DIPEA
(1.2 mg, 0.01 mmol). The mixture was stirred at room temperature for 12 hours under nitrogen and the solvent was removed in vacuo. The residue was dissolved in DCM (10 mL) and washed with water (5 mL x 2) and brine (5 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness in mow. The residue was dissolved in CI-130H
(5 mL), and aqueous LiOH (1.0 M, 2 mL) was added into the reaction mixture under nitrogen. The reaction mixture was stirred at room temperature for 24 hours.
The mixture was then neutralized with Dowex 50W resin, filtered and concentrated in vacua The residue was purified by HPLC to afford 15 (10.0 mg, 65% in two steps). 1H-NMR
(400 MHz, DMSO-d6): 6 (ppm) 7.85-7.76 (m, 3H, Aromatic), 7.72 (d, 1H, J= 8.0 Hz, ArH), 7.51 (d, 1H,./ = 8.0 Hz, ArH), 7.39 (s, 1H, triazole), 7.21 (d, 2H, ./ = 8.0 Hz, ArH), 7.13-7.03 (m, 4 II, MI), 5.96 (d, 1 H, J:::: 6.0 Hz, 1-H' (a thiol linkage), 4.96-4.91 (211, m), 4.71 (m, 2H, ArCH20), 4.55 (s, 2H, CH2-C=C), 4.45 (d, 1H, J= 8.4 Hz, 1-H()), 3.78-3.71 (5H, m), 3.69-3.67 (214, m), 3.43-3.31 (5H, m), 3.22-3.20 (m, 3H), 2.91-2.89 (m, IfI), 1.91 (2H, m). 13C NMR (100 MHz, DMSO-d6): ô (ppm) 143.3, 134.8, 133.1, 132.8, 131.9, 131.7, 131.0, 128.9 128.5, 127.9, 127.9, 126.7, 126.5, 126.1, 123.7, 123.6, 120.1, 120.0, 120.0, 119.5, 103.6(1-C (13)), 97.8 (1-C (a thiol linkage)), 81.5, 79.1, 77.3, 76.9, 75.7, 73.8, 73.1, 72.8, 70.6, 68.1, 64.3, 62.0, 48.7, 47.9, 28.5. HRMS (MALDI) miz Found:
784.2543, calculated: 784.2516 for C39H43N3011SNa [M+Na]+.
Thiomaltose has high specificity for bacteria over mammalian cells Thiomaltose-perylene has high specificity for bacteria over mammalian cells.
The uptake of thiomaltose-perylene was investigated in E .coli and in Raw 264.7 murine macrophages. A 500 IAL suspension of E .coli (0.D=0.6) was incubated with 20 ILM
thiomaltose-perylene for 2 hours. The bacterial cells were washed in PBS and lysed. The fluorescence intensity of the sample was measured and normalized to the protein content.
Similarly, i0 macrophagecells were incubated with 20 itM thiomaltose-perylene for 2 hours and the cells were lysed. The specificity of thiomaltose-perylene for bacteria was determined by comparing the fluorescence intensity in bacteria versus macrophages, normalized to intracellular protein content. Figures 13 indicates that thiomaltose-perylene has high specificity for bacteria, as the uptake of thiomal.tose-peryl.en.e was 98 fold higher in bacteria when compared to mammalian cells.
Thiomaltose is stable to maltase Thiomal.tose is stable to maltase hydrolysis. The stability of thiomaltose and maltose was investigated in the presence of maltase. Thiomaltose and maltose were incubated with 10 units of maltase, which is an enzyme that breaks maltose into two glucose molecules. The hydrolysis kinetics of thiomaltose and maltose was determined by quantifying the glucose released from thiomaltose or maltose hydrolysis.
Figure 14 demonstrates that thiomaltose is orders of magnitude more stable to maltase hydrolysis than maltose. For example, the half-life of maltose is approximately 30 minutes, under these conditions, whereas thiomaltose had negligible hydrolysis after 3 hours.
Synthesis of '8F-thiomaltose One can synthesize 18F-thiomaltose (17), following the general procedure shown in Figure 3. Briefly, one converts azido-thiomaltose (1.4) into a brosylate precursor (16) via a click reaction with pent-4-yn-1-y14-bromobenzenesulfonate (2). One obtains 18F-thiomaltose (17) by reacting the precursor (16) with KI8F, followed by deprotecti.on of the acetyl protecting groups with aqueous NaOH. One can purify intermediates by flash column chromatography on silica gel and characterized by NMR and FIRMS, and one can purify 18F-thiomaltose by HPLC.
Synthesis of thiomaltose-metronidazole TMM (14) One can conjugate metroin.adazole to thiomaltose and generate TMM (See Fig.
20).
To a stirred solution of thiomaltose imidate 9 (100 mg, 0.13 nunol) and metronidazole 12 (43 mg, 0.26 mmol.) in dry DCM (5 mL) was added 4A M.S. The mixture was stirred under nitrogen at 0 C for 1 hour. TMSOTf (10 tL, 0.044 nunol) was then added and the mixture was stirred at 0 "C for 2 hour. The reaction was quenched with Et3N and concentrated in vacuo. The residue was dissolved in Et0Ac (20 mL) and washed with water (5 mL
x 2) and brine (10 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/Et0Ac, 1:1) to afford 13 (53 mg, 52%). 1.FINMR. (400 MHz, CDCI.3): 6 (ppm) 7.95 (s, 1H), 5.87 (d, 1H), 5.28-5.16 (m, 2H), 5.07 (t, 1H) 4.98-4.94 (m, 1H), 4.74 (t, 1H), 4.64-4.56 (m, 2H), 4.39-4.32 (m, 3H), 4.24-4.08 (m, 6H), 3.86 (t, 1H), 3.59 (t, 1H), 2.95 (t, Iii), 2.46 (s, 3H), 2.14-1.95 (in, 21H). ES1-MS miz Found: 837.2286, calculated: 806,2284 for C321-144N3019S [Mi-H1+.
TN4M 14 was synthesized by deprotection of 13 with NaOH. To a stirred solution of 13 (40 mg, 0.005 mmol) in Me0H (2 mL) and water (0.5 nit) was added NaOH (40 mg, 1.0 mmol). The mixture was stirred overnight and purified by HPLC to afford TMIV1 (9.1 mg, 27.6%). 1H -NMR (400 MHz, D20): 6 (ppm) 8.39 (s, 1H), 5.50 (d, H), 4.24-4.15 (m, 3H), 4.04-3.95 (m, 214) 3.86-3.83 (m, 4H), 3.74-3.94 (m, 15I1), 3.26 (t, 211), 3.05 (t, 211), 2.67 (s, 5H), 2.56 (t, 2H). MALD1-MS m/z Found: 514.6, calculated: 512.1544 for C1811.30N3012S [M ; H]l.
TMM is effective at killing Giardia Methods for evaluating EC50 measurements in Giardia were established. Giardia cells were cultured in 96 well microtiter plates in anaerobic BD Bio-Bags (Becton Dickinson). Growth was assayed with a Moxi.Z coulter counter (Orfio Technologies). The TIMM and metroinadazole stock solutions contained DMSO to improve solubilit2,,,,. Giardia growth in 96 well plates with various volumes of TYDK media 10 and DMSO
concentrations were evaluated over several days at 37 C. Cells grew more consistently in higher volumes of media and noted reduced growth_ in DMSO concentrations above 0.25%.
Culture volumes of 180uL (10,000 cells/mL starting concentration) and the DMSO
concentrations at or below 0.1% were used. Growth was evaluated after 48 hours, The 48 hour time point allows several cell cycles of log phase growth, but stops before maximum densities of 1 x 106 cells/mL are reached TMM has an EC50 of 1.53 !Ai while metronidazole has an EC50 of 1.7 0,4 indicating that TMN4 is at least as good as metronidazole but appears more potent, thus demonstrating that thiomaltose conjugation does not interfere with the efficacy of metronidazole.
Synthesis of thiomaltose-radezolid (TMR) (14) The synthesis of a conjugate of thiomaltose and radezolid (TMR) is illustrated in Fig. 22, The synthesis of TMR is described below. To a stirred solution of 12 (8.0 tug, 0.02 trimol) and 13 (8.8 mg, 0.02 mmoi) in DMF (2 mL) was added DIPEA (50 .tL) and CuI (0.1 mg, 0.53 .tmol), after stirring for 24 1, the solvent was removed in vacuo. The crude product was purified by HPLC to afford thiomaltose-radezolid (TMR, 14) (12.0 mg, 71%). 1H NMR (400 MHz, 1)20): 6 (ppm) 8.06 (s, 1H), 7.56-7.33 (m, 6H), 7.21 (d, 11-1), 5.60 (d, 1H), 4.51 (t, 21-1), 4.40 (s, 1H) 4.33-4.20 (m, 4H), 4.11 (t, 1H), 3.92 (d., 2H), 3.85-3.70 (m, 7H), 3.60-3.33 (m, 8f1), 3.22-3.11 (in, 2H), 2.84 (s, 2H), 2.70 (t, 111), 2A8-2,07 (m, 2H), 1.98 (s, 3H), 1.34-1.27 (m, 2H). ESI-MS m/z Found: 837.3122, calculated:
837.3135 for C371-150FNI6013S [M I I]
TMR is more effective at killing P. aeruginosa than free radezolid The efficacy of radezolid can be increased by conjugating it to thiomaltose.
P.
aeruginosa (5x1.08CFUs) were incubated with various concentrations of either radezolid or TIsvIR and the MIC was determined via absorption measurements. The P.
aeruginosa strain used in this experiment was a clinical isolate, resistant to multiple antibiotics, obtained from a blood stream infection. Figure 23 shows data indicating that TM ft is 1-2 orders of magnitude more effective at killing pseudomonas than free radezolid. For example, a 0.5 uM concentration of TMR causes a 95% reduction in P. aeruginosa growth, whereas free radezolid had no efficacy up to a 10 WA concentration. Thus '[MR is able to improve the efficacy of radezolid, presumably by enhancing its transport into GNI3.
In certain embodiments, A must be S at least once or all of A are S.
In certain embodiments, n is 5 or 6 or more, or n is 3 or 4 or more.
In certain embodiments, R2, R3, and R4 are hydrogen or alkanoyl optionally substituted with R5.
In certain embodiments, Pi is hydrogen, halogen, or hydroxy substituted with a.
protecting group.
In certain embodiments, RI is 18F.
in certain embodiments, E is triazole positioned between linking groups such as the Wowing groups alone or in combination, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.
In certain embodiments, Ci is F.
Certain embodiments include compounds of Formula IA-1:
=.= P = 0 R-0 = . = A =
n' 0. .R1 \ 2 2 1 5R (IA-1), Wherein A is either S or 0, and A' is 0, provided that at least one A. is S.
In certain embodiments, n' 1 or 2, n' is 5 or 6 or more, or n' is 3 or 4 or more.
In certain embodiments, R2, R3, and R4 are hydrogen or alkanoyi optionally substituted with R5.
in certain embodiments, RI .is hydrogen, halogen, or h_ydroxyl, optionally substituted with a protecting group In certain embodiments, R' is '8F.
E is a linker, and in certain embodiments, E can be represented by a formula:
_____________ (CR'l R"1X1):(CR`2R"2X2)-(CR'R"YL __ wherein the symbol represents the point of attachement to A' and G;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'', R"', R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
XI, X2 and Y is each occurrence individually and independently -0-, -S-, -S-S-, -NH-, 4C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -SO2NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted lu.qerocyclyl, or absent;
q can be Ito 1000;
r can be I to 22.
In certain embodiments, E is triazole positioned between linking groups such as the following groups alone or in combination, ether, amine, amide, ester, carbonyl, thioi, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.
In certain embodiments, G is "F.
Certain embodiments include titioglycoside compounds of Formula 1A-2:
= 0 S = = = = = = = 0:.1= = = ...I = 0'E--G
fl I 2 ( IA-2), Wherein R'-R4, n', E and G are as defined above. In certain embodiments, R2, and Ware each hydrogen, and R' is either hydroxyl, hydrogen or halogen, preferably 18F.
In certain embodiments, the disclosure relates to compounds of formula I with formula 1B
R3 0 = TRIR"X)m 0 =
ri = R1.2 Formula 1B
or salts thereof wherein, A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R' and R" are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, -NHS02-, -S02NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be I to 1000;
r can be I to 22;
G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group;
RI, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkyithio, atkylamino, (alkyl)2arni no, alkylsulfinyi, alkylsulfonyi, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkyithio, alkylamino, (alkyOzarnino, alkylsuifinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifiuoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyi, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbarrtoy1, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylearbamoyi, methylthio, ethylthio, methylsulfinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-etitylsulfamoyl, N,N-dimethylsulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamo2,,,,I, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, X or Y is a di-substituted 1,2,3-triazole.
In certain embodiments, the compound of Formula 1B can be represented by the compound of Formula 113-1:
--- = Q 0 A N ,.1 ,, . -(CR R" X ),.õ. (CR2 R"2 X2 )-(CR`R"Y) =
0 Ri '2 R-(LB-1) or salts thereof wherein, A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
A' is 0;
11' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11., 12, 13, or 14;
rri' is 0, 1, 2, 3, 4, 5, 6, 7, 8,9. 10 I, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'1, R"1, R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X' is in each occurence absent;
X2 and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, 4C=0)S-, -SO-, -SO2, NFIS02-, -SO2NE1-,-(CH2C1120)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be I to 1000;
r can be 1 to 22;
G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group;
RI, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2arnino, alkylsulfinyi, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylatni no, (alky1)2arnino, alkykulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, a.cetylamino, Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethytthio, methylsulfinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfanioyl, N,N-diethylsuifamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, In certain embodiments, X2 is a di-substituted 1,2,3-triazote, in other embodiments, Y is absent, and in certain preferred embodiments, .X2 is a di-substituted 1,2,3-triazole and.
Y is absent.
in some embodiments, G can be the following:
U N R
=
. = == 0, 8 R
wherein the symbol $ represents the point of attachement to E;
U is N or CR";
W is N or CR9;
Z is a carbocyclic or heterocyclic ring;
R7 is alkyl., carbocyclyl, or aryl, wheren R7 is optionally substituted with one or more RI-3; or R7 and R11 form_ a heteroca.rbocyclic ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R? is a hydrogen or halogen;
R' is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen; and R'2 is hydrogen;
R13 is in each occurrence independently selected from halogen, nitro, cyano, hydrox.y, trifluoromethoxy, triftuoromethyl, amino, formyl, carbox.y, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethyla.mino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, -Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulla.moyl, N,N-diethyl.sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. In certain preferred embodiments, R7 is cyclopmpyl or phenyl, optionally substituted by one or more fluorine atoms.
In certain embodiments, Z can have the formula:
_________________ ,R R131 vvweyw :.,,.,....13 13 13 = N . = = N-1 R R ' )---ic N¨i = . R13 VA1/40,./ R13 R
I '''1/27'w i ,.: =
N ,r R ' = = is . N"--=
I ¨ ==. ..it I = = 11 R fõs = .= N-1 4e'N,µ, N--....,(/ N NH 1=3 R13 ="-- , 4Pe , R
, i ___________________________ NH R
13. .. = -R13 ._._N -----I N¨i 0 õ13 =
/
,R 3 = 13 == 13 = R .
or R R13 wherein the symbol 1 represents the point of attachement to E or or the quinolone fragment and R13 is as defined above. In preferred embodiments, ft" is in each case independently selected from hydrogen, methyl, or ethyl.
I 0 In some embodiments, G can be the following:
R'B R',.) 0 1¨N'it =
= . === ,`---0 Rio wi wherein the symbol i represents the point of attachement to E;
R7 is hydrogen, alkyl, carbocyclyl, or aryl, wheren R7 is optionally substituted with one OF
1 5 more, the same or different V;
R8, R9, Rip, and R" are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkan.oyl, carbamoyl, alkoxy, alkyithio, alkylamino, (alky1)2amino, alkyisulfinyl, alkylsuifonyl, arylsulfortyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, R.10, and R'' are optionally 20 substituted with one or more, the same or different, V;
R1 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mereapto, thrmyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocycly1 optionally substituted with one or more, the same or different, 1113;
R'3 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbarnoyl, rnercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethytamino, dimethytamino, diethytamino, N-methyl-N-ethylamino, acetylamino, -Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylearbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, eth:yrIthio, methylsuifinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-tnethylsulfanioyl, N-ethyisulfamoyl, N,N-dimethyisulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
It certain preferred embodiments, R.1-2 is acetylamitKL
In certain embodiments. G can he:
14; -(C1-12)xl8F, wherein x can be 1, 2, 3, 4, 5, 6, 7 or 8, S/7'33 /mt.
= 4. 4-Issu N = ."%s.1111 µ-:; = Yi¨NO2 = 7 = NH' HOOC
= NH NH . =
. = = 7. 1911 = =
==
or wherein the symbol represents the point of attachment to E.
For embodiments in which G is -(CH2)xl8F, it is preferred that p is 0.
In certain embodiments, the disclosure relates to compounds of formula 1 with formula IC, Vs() 2 1/ 1 6/114 4 8 4 6 PCT/US2015/051262 " ' ................... - E R12 7 tj NI R12 Mr' I 0 _R8 n Formula IC
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
E is a linking group;
Q is N in the ring of Z, or N is an amino or alkylamino group attached to the Z ring;
or Q is 0 of an oxygen attached to the Z ring, wherein the Z ring can be optionally substituted with one or more, the same or different, R13;
U is N or CR.11;
W is N or CR9;
Z is a carbocyclic or heterocyclic ring;
R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfin.yl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl., alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifi.uoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethyl.carbamoyl, N-m.ethyl-Nethylcarbamoyl, m.ethylthio, ethylthio, methylsulfinyl., ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is alkyl, carbocyclyl, or aryl, wheren. R7 is optionally substituted with one or more, the same or different R13; or R7 and Ri 1 form a heterocarboeyetie ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R9 is a hydrogen or halogen;
RIO is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen; and R12 is hydrogen;
R13 is halogen, nitro, cyano, hydroxy, triftuoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, di methytamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylearbamoyl, N-ethylearhamoy1, N,N-dimethylearbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylearbamoyl., methylthio, ethyl thio, methylsuifinyl., ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyi, ethoxycarbonyi, N-methyisulfamoyi, -N-ethyisulfamoyi, N,N-dimethyisulfamoyl, N,N-diethylsulfamo-yl, N-methyl-N-eth2,,,,Isulfamoyi, earboeyelyl, ary I, or heterocyclyl.
In certain embodiments, E is -(01.'R"X)m-(CR'R"Y)p- wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, lit, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R' and R" are at each occurrence individually and independently hydrogen, alkyl., halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-, -NH(C=0)-, (C=0)NEI- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -SO2N1-1-, -(C1-12CH20)q-, -(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disUbstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula !ID, R3 = 'CRR"X)m -(CFM"Y)p R7 j R12 (-) R1 L N U N
TR12 .'I 0 R8 Formula ID
or salts thereof wherein, U is N or CR11;
W is N or CR9;
A. is 0 or S at each occurrence provided A must be S at least once or all of A
are 51;
n is 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15;
rn. is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21., 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21., 22, or 23;
R.' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH--(0=0)-, -NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, NitS02-, -SO2NH-, 4CH2CF120)tr, -(0-12)r-, a disubstituted carhocycY., a di-substituted aryl, a disubstituted heterocyclyl, or absent;
ean be 1 to 1000;
r can be 1 to 22;
R1., R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyan , hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylarnino, (alky1)2amino, aikyisuifinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkyiamino, (alky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyt, amino, thrmyl, carboxy, carbamoyl, mercapto, sulfamoyl, 'methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylaini no, Nmethylearbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-methylthio, ethyithio, methylsultinyl, ethylsulfinyi, mesyl, ethylsulfbnyl, methoxycarbonyi, ethoxycarbonyi, N-methylsuifamoyl, N-ethylsulfamoyl, N,N-dimethylsuifamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylstilfamoyi, carbocyclyl, aryl, or heterocyclyl;
R7 is alkyl, carbocycl.2,,,,I, or aryl, wheren R7 is optionally substituted with one or more, the same or different R13; or R7 and R1 I form a heterocarbocyclic ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R9 is a hydrogen or halogen;
RIO is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen; and R12 is hydrogen;
R13 is halogen, nitro, cyano, hydroxy, tTifitioromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, niethylamino, ethytarnino, dimethylamino, diethytarnino, N-methyl-N-ethylamino, acetylamino, Nmeth.2,,,,Icarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-tnethyl-Nethylcarbamoyi, methylthio, ethylthio, methylsulfinyl., ethylsulfinyl, mesyl, ethylsuifonyl, meth.oxycarbonyl, ethoxycarbonyl, N-methyisulfamoyl, N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, the disclosure relates to compounds of formula I with formula = === A E ¨1\1 = = 111011 R
µ1\111N R- == = = = =
= = ilk 9 0 0 =ft.
1 fl = 1,/,-k Rio = = = im Lcss,R12 Formula IF
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15;
A is 0 or S at each occurrence provided A 'must be S at least once or all of A
are S;
E is a linking group; for example, of tbimula In certain embodiments, E can be 'represented by a formula:
_____________ (CR'1R"1 X1 ),(CRR"2X2)-(CR'R"Y),..) wherein the symbol represents the point of attachement to A and the triazoie m' is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R"1, R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
V is each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (CO)NH- -0(C-0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, -NHS02-, -SO2NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
X2 and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, 4C=0)S-, -SO-, -SO2, NFIS02-, -SO2NE1-,-(CH2C1120)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be 1 to 1000;
r can be 1 to 22;
R1, R2, R3, and R4, are each individually and independently hydrogen, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, aikyisuifinyl, alkylsulfortyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 arc optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, aLkylthio, alkyiamino, (alky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trilluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethytarnino, dimethyla.rnino, diethytarnino. N-methyl.-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethyl.carbamoyl, methylthio, ethylthio, m.ethylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is hydrogen, alkyl, carbocyclyl, or aryl, wheren R7 is optionally substituted with one or more, the sam.e or different R13;
R8, R9, R10, and R11 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl., carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfin.yl, alkylsulfonyl, arylsul.fonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, RIO, and R11 are optionally substituted with one or more, the same or different, R13;
R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl., carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, allcylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, su.lfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylarnino, dimethylarnino, diethylarnino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethyl.carbamoyl, N-methyl-N-ethylcarbamoyl., m.ethylthi.o, ethylthio, methyl.sulfi.nyl., ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, E is -(CR'R"X)m-(CR'R"Y)t, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
In certain embodiments, E is -(CH2)m- wherein m. is is I, 2, or 3.
R' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-, -NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, NHS02-, -S02NH-, -(CH2CH2O)q, -(CH2),-, a disubstituted carbocyclyl, a di-substituted.
aryl, a disubstituted h.cterocyclyl, or absent;
q can be Ito 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula. 1G.
N
.=
n Formula IC
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8, 9, .10, 11, 12, 13, 14, or 15;
A. is 0 or S at each occurrence provided A must be S at least once or all of .A are S;
E is a linking group; for example a formula:
_____________ (CR'l R"1X1 )(CR'2R"2X2)-(CR'R"Y), wherein the symbol represents the point of attachment to A and triazole;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3,4. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R"', It'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X1 is each occurrence individually and independently -0-, -S-, -S-S-, -(C-0)-, -NEI(C=0)-, (C=0)NII- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(0=0)S-, -SO-, -S02, -NEIS02-, -SO2NH-,-(CH2CH20)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
X2 and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, (0=0)MT.- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, NIIS02-, -SO2NE1-,-(CH2C1120)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyelyl, or absent;
q can be Ito 1000;
r can be 1 to 22;
G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest;
RI., R2, R3, and R4, are each individually and independently -(C=0)0CH2(C=0)alkyl, -0(C=0)0CH2(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, form.yl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyD2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R.1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylarnino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, aryl.sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R.6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylarnino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is -(C=0)0CH20(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, form.yl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;
R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyD2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl., carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R14;
R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluorom.ethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfln.yl, mesyl, ethylsulfonyl, m.ethoxycarbonyl, ethoxycarbonyl, N-meth.ylsulfamoyl, N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsulfamoyl, N-methyl-N-eth ylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, E is -(CR'R"X)m-(CR'R"Y)p- wherein iS I, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 74;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
In certain embodiments, E is -(CH2)m- wherein m is is 1, 2, or 3.
R' and R." are at each occurrence individually and independently hydrogen, alkyl., halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-, -N1-1(C=0)-, (C=0)NI-1- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -SO2NH-, -(CH2CH20)q-, -(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl., a disubstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula o R--0 = 0= == A E-N 1101 =
== = = = == = C S. = 110 Rio = = = = === = = = N
R2 0 ' =
Formula HI
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
A is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
E is a linking group;
R1, R2, R3, and R4, are each individually and independently independently--(C=0)0CH2(C=0)alkyi , -0(C=0)0CH2(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mereapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkyisulfinyl, alkylsuifortyl, arylsulfonyl, earbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the sam.e or different, R.6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethyl.carbamoyl, methylthio, ethylthio, m.ethylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;
R8, R.9, RIO, and R11 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyl.sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, RIO, and 111 I are optionally substituted with one or more, the same or different, R13;
R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;
R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl., carbocyclyl, atyl, or heterocyclyl optionally substituted with one or more, the same or different, R14;
R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylearbamoyl, N,N-diethylcarbamoyi, N-methyl-N-ethylcarbamoyl, methyltbio, ethytthio, methylsuifinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxyearbonyl, ethoxyearbonyi, N-methyisulfamoyi, N-ethy N,N-ditnethy N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
in certain embodiments, E is -(CR'R."X)m-(CR'R"Y)p- wherein m. is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
in certain embodiments, E is -(C11.2)m- wherein m is is 1, 2, or 3.
R' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH- , -(C=0)-, -NH(C=0)-, (C=0)NH- -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - -SO2N11-, 40-120-120)q-, -(CIE12)r-, a &substituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can. be 1 to 1000; and r can be 1 to 22.
In certain embodiments, the disclosure relates to compounds of fbrmula I with __ fot mula 1K, R4, = 8 R2 0[CH2jm-N
µ1\15-. N 11Z = = = = = 0 R10 = =1111r = N
Formula 1K
or salts thereof wherein, M is 2, 3, or 4;
R1, R2, R3, and R4, are each individually and independently -0(C=0)0CH20(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mereapto, fonnyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyistilfonyl, arykulfonyl, carbocyclyl, aryl, or heterocyelyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the sam.e or different, R.6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethyl.carbamoyl, methylthio, ethylthio, m.ethylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, R7 is ---(C=0)0CH20(C=0)a1kyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R13;
R8, R.9, RIO, and RI I are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyl.sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R8, R9, RIO, and Ri I are optionally substituted with one or more, the same or different, R13;
R12 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13;
R13 is hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl., carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R14;
R14 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, m.ercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethyicarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyi, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsuifinyl, ethylsulfinyi, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyi, N-methyisulfamoyi, N-ethylsulfamoyi, N,N-ditneth.yisulfamoyi, N,N-diethylsulfamoyi, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, in certain embodiments, the disclosure relates to compounds of fbrmula I with fotmula IL, o ***, 0 N
R3-0 = I.== A -E-N
0 =
F! = 1 n 02 Formula IL
or salts thereof wherein, n is 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15;
A. is 0 or S at each occurrence provided A must be S at least once or all of A
are S;
E is a linking group; for example a formula:
__________________________________________ (CR'1 R"1 X1)(CR'2R"2x2)---(CR'R"Y);
N;vherein the symbol represents the point of attachem.ent to A and imidazole;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
WI, R'2 and 1Z."2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X' is each occurrence individually and independently -0-, -S-, -S-S-, _(CO)_, -NH(C=0)-, (C=0)NH-, -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -SO2, -NEIS02-, -SO2NH-, -(CH2CH20)(4-,-(Cli2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
X2 and Y are at each. occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C=0)-,-NH(C=0)-, -0(C=0)-, -(C=0)0-, -S(C=0)-, -(C=0)S-, -SO-, -S02, - NHS02-, -S02NH-, -(CH2CH20)q-, -(Cf12),, a disubstituted carbocyclyl, a di-substituted aryl, a &substituted heterocyclyl, or absent;
q can be 1 to 1000;
r can be Ito 22;;
R1, R2, R3, and R.4, are each individually and independently -(C=0)0CH20(C=0)alkyl, -0(C=0)0CH20(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, form.yl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyD2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R.1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylarnino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, aryl.sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylarnino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylarnino, acetylamino, Nmethylcarbamoyl., N-ethylcarbamoyl, N,N-dimethylcarbamoyl., N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, meth.oxycarbonyl, eth.oxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
In certain embodiments, E is -(CR'R"X)in-(CR'R"Y)p- wherein m is 1., 2, 3, 4, 5, 6, 7, 8, 9, 10 ,11, 12, 13, 14, 1.5, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
In certain embodiments, E is -(CH2)m- wherein m is is I, 2, or 3.
R' and R" are at each occurrence individually and independently hydrogen, alkyl, halogen, or hydroxyl;
X and Y are at each occurrence individually and independently -0-, -S-, -S-S-, -NH-, -(C...0)-, -NFI(C=0)-, (C...0)NH-, -0(0=0)-, -(C=0)0-, -S(C:=0)-, -(C....0)S-, -SO-, -S02, - NHS02-, -SO2NH-, -(CH2CH20)q-, -(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be Ito 22.
In certain embodiments, the disclosure relates to compounds of formula I with formula IK, R=,-) = = =====
== = 1 S = = = = 0 R2 = =.'= 0[CH2.]ril-N
Formula 1K
or salts thereof wherein, al is 2, 3, or 4;
RI, R2, R3, and R4, are each individually and independently ---0(C=0)0C1-120(C=0)alkyl, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, atkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyisulfonyi, arylsultbnyl, carbocyclyl, aryl, or heterocyclyl, wherein each RI, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, rhercapto, formyl, carboxy, earbamoyl, alkoxy, alkylthio, alkyiamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6; and R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, thrmyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, etboxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylatni no, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbanioyl, methylthio, ethyithio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-tnethylsulfamoyl, N-ethyisulfamoyi, N,N-dimethyisulfamoyi, N,N-diethylsuifamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, awl, or heterocyclyl.
In certain embodiments, the disclosure relates to a composition comprising a compound of formula if:
= = 0 Formula II
or derivatives thereof wherein, A is 0, NH, S or a direct bond to R8;
RI., R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen, hydroxy, mercapto, halogen, amino, alkyl, alkoxy, tracer, 18F optionally substituted with a protecting group or optionally substituted with one or more, the same or different, R9;
R8 is E-G, wherein E is a linking group; G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest; or R8 is a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkyl.amino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R9;
R9 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R1.0 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, allcylarnino, (alky1)2arnino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R1.1 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylami.no, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R.12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylami.no, (alkyl.)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the sam.e or different, R.13; and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylarnino, dimethylarnino, diethylamino, N-methyl-N-ethylarnino, acetylarnino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-inethylsulfamoyl, N-ethylsulfamoyl, N,N-dimetitylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, earbocyclyi, aryl, or heteroeyelyi.
In certain embodiments, R1, R2, R3, R4, R5, R6, and R7 are, the same or different -0(C=0)0CH20(C=0)alkyl, hydrogen, hydroxy, mercapto, halogen, amino, alkyl, alkoxy, tracer, '8F optionally substituted with a protecting group or optionally substituted with one or more, the same or different, R9.
In certain embodiments, the disclosure relates to compounds of formula II with formula HA, =
=
Formula IIA
or derivatives thereof wherein, A is 0, NH, S or a direct bond to R8;
RI, R2, R.3, R4, R5, R6, and R7 are, the same or different, hydrogen or a protecting group;
R8 is E-G, wherein E is a linking group; (ii is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest; or R8 is a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alky1)2amino, alkylsulfinyl, alkyisulfonyi, arylsultbnyl, carboeyelyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R9;
R9 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkytamino, (a1ky1)2atnino, alkylsulfonyl, aryisuifonyl, carbocyciyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
RIO is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (a.lky1)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein RIO
is optionally substituted with one or more, the same or different, R.11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylami.no, (alkyl)zamino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the sam.e or different, R.12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthi.o, alkylami.no, (alkyl.)2amino, alkylsu.lfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the sam.e or different, R.13; and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluorom.ethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylarnino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsu.lfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
R1, R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen or -(C...0)0CI-12(0=0)alkyl.
Pharmaceutical Formulations Within certain embodiments, the disclosure contemplates compounds and conjugates disclosed herein in pharmaceutical composition, optionally as a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable excipient. Pharmaceutical compositions of the compounds of this application, or derivatives thereof, can be formulated as solutions or lyophilized powders for parenteral administration. Powders can be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic aqueous solution. Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral administration but can also be used for oral administration. Excipients, such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate, can also be added.
Alternatively, these compounds can be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols or water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier can also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation can be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. Such a liquid formulation can be administered directly p.o. or filled into a soft gelatin capsule.
The pharmaceutical compositions of the application can be in the form of a sterile injectable preparation. Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
In some cases, protective groups can be introduced and finally removed.
Certain "protective groups" such as an N-acetyl group, can be incotporated and remain as part of the desired compound. Suitable protective groups for amino, hydroxy and carboxy groups are described in Greene et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991. Standard organic chemical reactions can be achieved by using a number of different reagents, for examples, as described in Larock:
Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
Radio-labeling a small molecule, such as a compound of the present application, usually involves displacement of a suitably activated precursor with a radioactive moiety in a compatible reaction media. In the case of 18F-labeling, the [18F]fluoride attachment to the precursor occurs via n.ucleophilic substitution of a leaving group, such as mesylate, tosylate, bromide, iodide or diazonium salt, or nitro group. Depending on the compound, the preparation of a radio-labeled compound generally consists of at least two steps. The first step involves the preparation of radiol.abeling precursor, in which various functional groups have been appropriately protected and a proper leaving group has been incorporated. The second sequence then involves the radio-labeling, and removal of the protecting group as known in the art Terms As used herein, "alkyl" means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from. 1 to 10 carbon atoms, while the term "lower alkyl" or "Cl- 4 alkyl" has the same meaning as alkyl but contains from 1 to 4 carbon atoms. The term "higher alkyl" has the sam.e meaning as alkyl but contains from 7 to 20 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n hexyl, n-septyl, n-octyl, n-nonyl., and the like;
while saturated branched al.kyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2- butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl.-2-butenyl., 2,3-dimeth.y1-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- methyl-l-butynyl, and the like.
Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles"
or "carbocycl.y1" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.
"Heterocarbocycles" or heterocarbocycly1" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which can be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatorns can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. Heterocarbocycl.es include morpholinyl, pyrrol.idinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofmnyl, tetrahydropyranyl., tetrahydropyrid.inyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
"Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems can, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.
As used herein, "heteroaryl" refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems can, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl., isooxazolyl, benzoxazolyl, pyrazolyl, irnidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl"
includes N-alkylated derivatives such as a 1-methylimidazol-5-ylsubstituent.
As used herein, "heterocycle" or "heterocycly1" refers to mono- and polycycl.ic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. The mono- and polycycli.c ring systems can be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycl.es, heteroaryls, and the like.
"Allcylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., -S-C113).
"Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n.-propoxy, propoxy, n-butoxy, s-butoxy, t-butoxy.
"Alkylamino" refers an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH3).
"Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bride (i.e., -(C=0)alkyl).
"Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., -S(=0)2alkyl) such as mesyl and the like, and "Arylsulfonyl"
refers to an aryl attached through a sulfonyl bridge (i.e., - S(=0)2a1y1).
"Allcylsulfinyl" refers to an alkyl as defined above attached through a sulfinyl bridge (i.e. -S(=0)alkyl.).
The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents."
The molecule can be multiply substituted. In the case of an oxo substi.tuent ("=0"), two hydrogen atoms are replaced. Example substituents within this context can include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=0)Rb, -NRaC(=0)NRaNRb, -NRaC(=0)0Rb, NRaSO2Rb, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRb, -0C(=0)NRaRb, -0Ra, -SRa, -SORa, S(=0)2Ra, -0S(=0)2Ra and -S(=0)20Ra. Ra and Rb in this context can be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
The term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.
As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
As used herein, the term "combination with" when used to describe administration with an additional treatment means that the agent can be administered prior to, together with, or after the additional treatment, or a combination thereof.
As used herein, "salts" refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylarnines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. In preferred embodiment the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
"Subject" refers any animal, preferably a human patient, livestock, rodent, monkey or domestic pet.
As used herein, the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analog. The derivative can be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen and hydrogen or replacing an amino group with a hydroxyl group or vice versa. The derivative can be a prodrug. Derivatives can be prepare by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry text books, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.
As used herein, the term "saccharide" refers to sugars or sugar derivatives, polyhydroxylated aldehydes and ketones, e.g., with an empirical formula that approximates Cm(H20)n, i.e., wherein m and n are the same or about the same. Contemplated saccharides include, e.g., maltose, isomaltose, and lactose with an. empirical formula of Cl2H22011. The term is intended to encompass sugar monomers, oligomers, and polymers. The terms oligosaccharide and pol.ysaccharide are used interchangeably, and these saccharides typically contain between two and ten monosaccharide units, or greater than ten monosaccharid.e units. In certain embodiments of the disclosure, the saccharide is a dextrin, maltodextrin, or cyclodextrin. Dextrins are mixtures of polymers of D-glucose units linked by a-(1¨>4) or a-(1¨>6) glycosidic bonds. Maltodextrin consists of D-glucose units connected in chains of variable length. The glucose units are primarily linked with a(I ¨>4) glycosidic bonds. Maltodextrin is typically composed of a mixture of chains that vary from three to nineteen glucose units long. Maltose is a disaccharide formed from two units of glucose joined with an a(1¨>4)bond. Isomaltose has two glucose molecules linked through an. a(1¨>6) bond. In certain. embodiments, the disclosure contemplates cyclic and non-cyclic polysaccharides. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, such as alpha cyclodextrin; a six membered sugar ring molecule; beta cyclodextrin, a seven sugar ring molecule; and gamma cyclodextrin, an eight sugar ring molecule.
The term "thiomal.tose" and "thiomaltose" analogs refers to maltose, saccharides, or polysaccharides, wherein one or more to the sugar units are connect by a bridging thiol. In certain embodiments, the sugar units are glucose bridged by thiol through a 1-4 and or 1¨+6 bond.
As used herein, the term "conjugate" or "conjugated," and the like refer to molecular entities being linked together through covalent bonds. Conjugation can be accomplished by directly coupling the two molecular entities, e.g., creating an ester or amide from a hydroxyl group, amino group, and a carboxylic acid. Conjugation can be accomplished by indirectly coupling the two molecular entities, e.g., instituting a linking group such as a polyethylene glycol. Conjugation can be accomplished by modifying the molecular entities with chemical groups that react with one another, e.g., allcyne-functionalized entity with an azide-functionalized entity or the reduction of thiol groups on individual entities to form a disulfide bond.
"Positron emission tomography (PET) refers to an imaging technique that produces a three-dimensional image by detecting pairs of gamma rays emitted indirectly by a positron-emitting radionuclide tracer. Three-dimensional images of tracer concentration within the area are then constructed by computer analysis. A. radioactive tracer is administered to a subject e.g., into blood circulation. Typically there is a waiting period while tracer becomes concentrated in areas of interest; then the subject is placed in the imaging scanner. As the radioisotope undergoes positron emission decay, it emits a positron, an antiparticle of the electron with opposite charge, until it decelerates to a point where it can interact with an electron, producing a pair of (gamma) photons moving in approximately opposite directions. These are detected in the scanning device.
The technique typically utilizes simultaneous or coincident detection of the pair of photons moving in approximately opposite direction (the scanner typically has a built-in slight direction-error tolerance). Photons that do not arrive in pairs (i.e. within a timing-window) are typically ignored. One typically localizes the source of the photons along a straight line of coincidence (also called the line of response, or LOR). This data is used to generate an image.
The term "radionuclide" or "radioactive isotope" refers to isotopes exhibiting radioactive decay (i.e., emitting positrons) and radiolabeling agents comprising a radioactive isotope (e.g., [11C]methane, [11C]carbon monoxide, [11C]carbon dioxide, r11 Ciphosgene, [11C]urea, [11C]cyanogen bromide, as well as various acid chlorides, carboxylic acids, alcohols, aldehydes and ketones containing carbon-11). Such isotopes are also referred to in the art as radioisotopes or radionuclides. Radioactive isotopes are named herein using various commonly used combinations of the name or symbol of the element and its mass number (e.g., 18F, F-18, or fluorine-18). Exemplary radioactive isotopes include 1-124, F-18 fluoride, C-11, N-13, and 0-15, which have half-lives of 4.2 days, 110 minutes, 20 minutes, 10 minutes and 2 minutes, respectively. The radioactive isotope is preferably dissolved in an organic solvent, such as a polar aprotic solvent.
Preferably, the radioactive isotopes used in the present method include F-18, C-11, 1-123, 1-124, 1-127, 1-131, Br-76, Cu-64, Tc-99m, Y-90, Ga-67, Cr-51, Ir-192, Mo-99, Sm-153 and II-201. Other radioactive isotopes that can be employed include: As-72, As-74, Br-75, Co-55, Cu-61, Cu-67, Ga-68, Ge-68, 1-125, 1-132, In-111, Mn-52, Pb-203 and Ru-97.
Other methods of preparing radiolabeled ligands are well known in the art.
Example of such methods are disclosed in, for example: 1) Jewett, D. M. (1992) A
Simple Synthesis of[IC]Methyl Triflate Appl. Radiat. Isot. 43, 1383-1385; 2) Crouzel, C.
Langstrom, B., Pike, V. W., and Coenen, H. H. (1987) Recommendations for a practical production of [ 1C]methyl iodide Appl. Radiat. Isot. Int. J. Appl. Instrum. Part A 38, 601-603; Dannals, R.
F., Raven, H. T.; 3) Wilson, A. A. (1990) Radiochemistry of Tracers for Neurotransmitter Receptor Studies. In: Quantitative Imaging: Neuroreceptors, Neurotransmitters, and Enzymes. (Edited by Frost), J. J. Wagner Jr., H. N. pp. 19-35, Raven Press, New York; 4) Jewett, D. M., Manger, T. J., and Watkins, G. L. (1991) Captive Solvent Methods for Fast Simple Carbon-11 Radioalkylations. In: New Trends in Radiopharrnaceutical Synthesis, Quality Assurance and Regulatory Control (Edited by Emran, A. M.) pp. 387-391.
Plenum Press, New York; 5) Marazano, C., Maziere, M., Berger, G., and Comar, D.
(1977) Synthesis of methyl iodide-11C and formaldehyde-11C. Appl. Radiat. Isot.
28, 49-52;
6) Watkins, G., Jewett, D., Mulholland, G., Kitboum, M., and Toorongian, S.
(1988) A
Captive Solvent Method for Rapid N-[ 1C]Methylation of Secondary Amides Application to the Benzodiazepine, 4'-Chlorodiazepam (R05-4864) Appl. Radiat. Isot. 39, 441-444; and 7) Wilson, A. A., DaSilva, J. N., and Houle, S. (1996) In vivo evaluation of [
IC] and ['5F]-labeled cocaine analogs as potential dopamine transporter ligands for positron emission tomography Nucl. Med. Biol. 23, 141-146. The subject matter of all references cited herein are incorporated herein by reference in their entirety.
As used herein, a "linker" refers to any molecular configuration that joins molecular moieties. It includes molecules with covalent and non-covalent interactions. A
prefer linker is a polymer, i.e., molecule with repeated linking moieties. The linked moieties can be identical in structure or vary, e.g., copolymers. Linking polymers include, but are not limited to, biological polymers, polyethylene glycols, hydrocarbon chains, alkylacrylates, alkylacrylamides, amides, esters, polypeptides, and derivatives thereof A "protecting group" refers to those moieties that are introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction or to facilitate purification. Protecting groups can be categorized by the reaction conditions and/or reagents that are used to remove them such as acid labile protecting groups, base labile protecting groups and hydrogenation removable protecting groups. For example, acid labile protecting groups, such as tBu or Boc, typically decompose when exposed to strong acidic conditions providing a hydrogen substituent in place of tBu or Boc protecting group. .Acetyi esters and thioesters of alcohols and thiols are examples of base labile protecting groups. Additional examples of protecting groups include, but are not limited to, 4-methoxy-2,3,6-trimethylphenypsullonyl (Mtr), 2,2,5,7,8-pentamethyl-chroman-6-sulphonyl (Pm.c), tosyl (Tos), mesitylenesulfonyi (Mts), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyi (Tmob), tripheylmethyi (Trt), 9-fiuorenytmethyloxycarbortyl (fmoc), tert-butyl (tBu), benzyl (Bzi), t-butoxymethyl ether (Bum), (2,4-dinitrophenol) Dnp, benzyloxymethy1 (Born), benzyloxycarbonyl (Z), 2-chloro--benzyloxycarbonyl (CAZ), t-butyloxycarbonyl (Boc), form.yi (CHO) or 2-bromobenzyloxycarbonyl (BrZ) and heterocycles such as succinimide, maleimide, and 'ph.athalimide. Protecting groups can be in the form of derivatives, e.g., having one or more substituents.
EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and therapeutic methods of the disclosure, and are not intended to limit the scope of what the claimed embodiments.
Synthesis of thiomaltose-perylene In order to test the specificity of thiomaltose for bacteria, a thiomaltose derivative labeled with the fluorescent dye was synthesized., perylene (15), using an a.zido-thiomaltose (14) as the synthetic intermediate. The procedure used for the synthesis of thiomaltose-'perylene (15) is shown in Figure 2. .Azido-thiornaltose (14) was first synthesized by lewis acid promoted glycosylation between the thiomaltose imidate donor (13) and a.zidopropanol. Thiomaltose-perylene was then synthesized by conjugating the perylene dye onto azidothiomaltose (14) via the click reaction, followed by deprotection of the acetyl protecting groups using lithium hydroxide. Synthetic details for the synthesis of thiomaltose (10), azidothiomaitose (14) and thiomaltose-perylene (15) are provided.
Synthesis of thiomaltose (10) To a stirred solution of a-D-glucopyranose, 4-S-(2,3,4,6-tetra-0-acety1-13-D-glucopyranosyl)-4-thio-1,2,3,6-tetrabenzoate 9 (,0 g, 10 rnmol) in anhydrous CH3OH (15 nit) was added NaOCH3 (100 mg, 20 mmol) under an atmosphere of N2 at room temperature, and the reaction was stirred at room temperature for 12 hours.
The reaction mixture was neutralized by adding acidic DOWEX resins, filtered, and concentrated in vacuo. The resulting residue was re-dissolved in DIVIF (10 mL), and precipitated by adding ether (100 mL). The precipitated powder was collected and dried in vacuo to afford the product 10 (300 mg, 83%) (a and 13 mixture). '1-1 NMR (D20, 400 MHz): 6 (ppm) 5.01 (d, 3./(H,H) = 10,2 Hz, 0.6H), 4.82 (d, 3./(H,H) = 4,8 Hz, 1H), 4.33 (d, 3./
(F1,11) = 3.6 Hz, 0.4H), 3.71-3.74 (m, 2H), 3.67-3.63 (m, 3H), 3.5-3.49 (m, 2H), 3.43 (dd. 3./(1-1,H) = 10.2 Hz, 1H), 3.26-3.21 (m., 311), 3.0-2.98 (m, 1H), 2.83-2.85 (in, 11-1). 13C NMR
(1)20, 100 MHz): 8 (ppm) 95.8, 91.5, 85.2, 85.1, 85.1, 81.2, 80.0, 79.6, 78.5, 77.9, 77.8, 77.0, 76.8, 75.8, 74.3, 74.1, 73.7, 73.1, 70.8, 62.8, 62.7, 62.2, 61.5, 48.1, 47.5. MS
(MALDI) m/z Found: 381.79, calculated: C12H22010SNa [M+Na ] 381.08.
Synthesis of azidothiomaltose (14) To a stirred solution of thiamaitose imidate 13 (0.16 g, 0.2 tranol) and 3-azidopropanol (0.1 g, 1,0 mmol) in dry DCM (5 nit) was added 4A M.S. The mixture was stirred under nitrogen at 0 "C for 1 hour. TMSOTf (45 4, 0.20 mmol) was then added and the mixture was stirred at 0 "C for 2 hour, The reaction was quenched with Et3N and.
concentrated in vacuo. The residue was dissolved in Et0Ac (20 rnL) and washed with water (5 ml, x 2) and brine (10 mt), The organic phase was dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue was purified by flash column chromatography on silica gel (h.exane/Et0A.c, 1:1) to afford 14 (92.6 mg, 63%). '11. NMR (400 Pv1Hz, CDC13): 6 (ppm) 5.89 (d, 1 H, J = 5.8 Hz, 1-H (a thiol linkage)), 5.28-5.21 (m, 2H), 5.06 (1H, m), 4.95 (111, m), 4.78 (1H, m), 4.65 (1H, in), 4,46 (1H, d,J= 8.6 Hz, 1.-H (13)), 4.33 (1H, m), 4.25-4.20 (2H, m), 4.11 (1H, m), 3.89 (1H, in), 3.58-3.63 (2H, m), 3.35 (2H, t, J=
6.0 Hz, CH2), 2.97 (2H, t, J= 6.0 Hz, CH2), 2.12-1.99 (s, 21 1-1, CH3), 1.83 (2H, m, CH2).
13CNMR. (100 MHz, CDCI.3): 6 (ppm) 170,5, 170,4, 170.2, 169.9, 169.8, 169.5, 169.4, 100.3, 82.4, 76.7, 75.7, 72.7, 72.5, 70.3, 70.1, 69.7, 68.6, 67.9, 66.3, 63.6, 61.5, 47.9, 43.7, 28.9, 20.8, 20.7, 20.6, 20.6, 20.5, 20.4. HRMS (MALDI) m/z Found: 758.2089, calculated:
758.2054 for C29H4iN3017SNa [M+Na]-F.
Synthesis of thiomaltose-perylene (15) To a stirred solution of 14 (15.0 mg, 0.02 mmol) and alkyne functionalized perylene dye (13.0 mg, 0.04 mmol) in DM? (5 mL) was added Cul (0.2 mg, 1.0 iumol) and DIPEA
(1.2 mg, 0.01 mmol). The mixture was stirred at room temperature for 12 hours under nitrogen and the solvent was removed in vacuo. The residue was dissolved in DCM (10 mL) and washed with water (5 mL x 2) and brine (5 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness in mow. The residue was dissolved in CI-130H
(5 mL), and aqueous LiOH (1.0 M, 2 mL) was added into the reaction mixture under nitrogen. The reaction mixture was stirred at room temperature for 24 hours.
The mixture was then neutralized with Dowex 50W resin, filtered and concentrated in vacua The residue was purified by HPLC to afford 15 (10.0 mg, 65% in two steps). 1H-NMR
(400 MHz, DMSO-d6): 6 (ppm) 7.85-7.76 (m, 3H, Aromatic), 7.72 (d, 1H, J= 8.0 Hz, ArH), 7.51 (d, 1H,./ = 8.0 Hz, ArH), 7.39 (s, 1H, triazole), 7.21 (d, 2H, ./ = 8.0 Hz, ArH), 7.13-7.03 (m, 4 II, MI), 5.96 (d, 1 H, J:::: 6.0 Hz, 1-H' (a thiol linkage), 4.96-4.91 (211, m), 4.71 (m, 2H, ArCH20), 4.55 (s, 2H, CH2-C=C), 4.45 (d, 1H, J= 8.4 Hz, 1-H()), 3.78-3.71 (5H, m), 3.69-3.67 (214, m), 3.43-3.31 (5H, m), 3.22-3.20 (m, 3H), 2.91-2.89 (m, IfI), 1.91 (2H, m). 13C NMR (100 MHz, DMSO-d6): ô (ppm) 143.3, 134.8, 133.1, 132.8, 131.9, 131.7, 131.0, 128.9 128.5, 127.9, 127.9, 126.7, 126.5, 126.1, 123.7, 123.6, 120.1, 120.0, 120.0, 119.5, 103.6(1-C (13)), 97.8 (1-C (a thiol linkage)), 81.5, 79.1, 77.3, 76.9, 75.7, 73.8, 73.1, 72.8, 70.6, 68.1, 64.3, 62.0, 48.7, 47.9, 28.5. HRMS (MALDI) miz Found:
784.2543, calculated: 784.2516 for C39H43N3011SNa [M+Na]+.
Thiomaltose has high specificity for bacteria over mammalian cells Thiomaltose-perylene has high specificity for bacteria over mammalian cells.
The uptake of thiomaltose-perylene was investigated in E .coli and in Raw 264.7 murine macrophages. A 500 IAL suspension of E .coli (0.D=0.6) was incubated with 20 ILM
thiomaltose-perylene for 2 hours. The bacterial cells were washed in PBS and lysed. The fluorescence intensity of the sample was measured and normalized to the protein content.
Similarly, i0 macrophagecells were incubated with 20 itM thiomaltose-perylene for 2 hours and the cells were lysed. The specificity of thiomaltose-perylene for bacteria was determined by comparing the fluorescence intensity in bacteria versus macrophages, normalized to intracellular protein content. Figures 13 indicates that thiomaltose-perylene has high specificity for bacteria, as the uptake of thiomal.tose-peryl.en.e was 98 fold higher in bacteria when compared to mammalian cells.
Thiomaltose is stable to maltase Thiomal.tose is stable to maltase hydrolysis. The stability of thiomaltose and maltose was investigated in the presence of maltase. Thiomaltose and maltose were incubated with 10 units of maltase, which is an enzyme that breaks maltose into two glucose molecules. The hydrolysis kinetics of thiomaltose and maltose was determined by quantifying the glucose released from thiomaltose or maltose hydrolysis.
Figure 14 demonstrates that thiomaltose is orders of magnitude more stable to maltase hydrolysis than maltose. For example, the half-life of maltose is approximately 30 minutes, under these conditions, whereas thiomaltose had negligible hydrolysis after 3 hours.
Synthesis of '8F-thiomaltose One can synthesize 18F-thiomaltose (17), following the general procedure shown in Figure 3. Briefly, one converts azido-thiomaltose (1.4) into a brosylate precursor (16) via a click reaction with pent-4-yn-1-y14-bromobenzenesulfonate (2). One obtains 18F-thiomaltose (17) by reacting the precursor (16) with KI8F, followed by deprotecti.on of the acetyl protecting groups with aqueous NaOH. One can purify intermediates by flash column chromatography on silica gel and characterized by NMR and FIRMS, and one can purify 18F-thiomaltose by HPLC.
Synthesis of thiomaltose-metronidazole TMM (14) One can conjugate metroin.adazole to thiomaltose and generate TMM (See Fig.
20).
To a stirred solution of thiomaltose imidate 9 (100 mg, 0.13 nunol) and metronidazole 12 (43 mg, 0.26 mmol.) in dry DCM (5 mL) was added 4A M.S. The mixture was stirred under nitrogen at 0 C for 1 hour. TMSOTf (10 tL, 0.044 nunol) was then added and the mixture was stirred at 0 "C for 2 hour. The reaction was quenched with Et3N and concentrated in vacuo. The residue was dissolved in Et0Ac (20 mL) and washed with water (5 mL
x 2) and brine (10 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/Et0Ac, 1:1) to afford 13 (53 mg, 52%). 1.FINMR. (400 MHz, CDCI.3): 6 (ppm) 7.95 (s, 1H), 5.87 (d, 1H), 5.28-5.16 (m, 2H), 5.07 (t, 1H) 4.98-4.94 (m, 1H), 4.74 (t, 1H), 4.64-4.56 (m, 2H), 4.39-4.32 (m, 3H), 4.24-4.08 (m, 6H), 3.86 (t, 1H), 3.59 (t, 1H), 2.95 (t, Iii), 2.46 (s, 3H), 2.14-1.95 (in, 21H). ES1-MS miz Found: 837.2286, calculated: 806,2284 for C321-144N3019S [Mi-H1+.
TN4M 14 was synthesized by deprotection of 13 with NaOH. To a stirred solution of 13 (40 mg, 0.005 mmol) in Me0H (2 mL) and water (0.5 nit) was added NaOH (40 mg, 1.0 mmol). The mixture was stirred overnight and purified by HPLC to afford TMIV1 (9.1 mg, 27.6%). 1H -NMR (400 MHz, D20): 6 (ppm) 8.39 (s, 1H), 5.50 (d, H), 4.24-4.15 (m, 3H), 4.04-3.95 (m, 214) 3.86-3.83 (m, 4H), 3.74-3.94 (m, 15I1), 3.26 (t, 211), 3.05 (t, 211), 2.67 (s, 5H), 2.56 (t, 2H). MALD1-MS m/z Found: 514.6, calculated: 512.1544 for C1811.30N3012S [M ; H]l.
TMM is effective at killing Giardia Methods for evaluating EC50 measurements in Giardia were established. Giardia cells were cultured in 96 well microtiter plates in anaerobic BD Bio-Bags (Becton Dickinson). Growth was assayed with a Moxi.Z coulter counter (Orfio Technologies). The TIMM and metroinadazole stock solutions contained DMSO to improve solubilit2,,,,. Giardia growth in 96 well plates with various volumes of TYDK media 10 and DMSO
concentrations were evaluated over several days at 37 C. Cells grew more consistently in higher volumes of media and noted reduced growth_ in DMSO concentrations above 0.25%.
Culture volumes of 180uL (10,000 cells/mL starting concentration) and the DMSO
concentrations at or below 0.1% were used. Growth was evaluated after 48 hours, The 48 hour time point allows several cell cycles of log phase growth, but stops before maximum densities of 1 x 106 cells/mL are reached TMM has an EC50 of 1.53 !Ai while metronidazole has an EC50 of 1.7 0,4 indicating that TMN4 is at least as good as metronidazole but appears more potent, thus demonstrating that thiomaltose conjugation does not interfere with the efficacy of metronidazole.
Synthesis of thiomaltose-radezolid (TMR) (14) The synthesis of a conjugate of thiomaltose and radezolid (TMR) is illustrated in Fig. 22, The synthesis of TMR is described below. To a stirred solution of 12 (8.0 tug, 0.02 trimol) and 13 (8.8 mg, 0.02 mmoi) in DMF (2 mL) was added DIPEA (50 .tL) and CuI (0.1 mg, 0.53 .tmol), after stirring for 24 1, the solvent was removed in vacuo. The crude product was purified by HPLC to afford thiomaltose-radezolid (TMR, 14) (12.0 mg, 71%). 1H NMR (400 MHz, 1)20): 6 (ppm) 8.06 (s, 1H), 7.56-7.33 (m, 6H), 7.21 (d, 11-1), 5.60 (d, 1H), 4.51 (t, 21-1), 4.40 (s, 1H) 4.33-4.20 (m, 4H), 4.11 (t, 1H), 3.92 (d., 2H), 3.85-3.70 (m, 7H), 3.60-3.33 (m, 8f1), 3.22-3.11 (in, 2H), 2.84 (s, 2H), 2.70 (t, 111), 2A8-2,07 (m, 2H), 1.98 (s, 3H), 1.34-1.27 (m, 2H). ESI-MS m/z Found: 837.3122, calculated:
837.3135 for C371-150FNI6013S [M I I]
TMR is more effective at killing P. aeruginosa than free radezolid The efficacy of radezolid can be increased by conjugating it to thiomaltose.
P.
aeruginosa (5x1.08CFUs) were incubated with various concentrations of either radezolid or TIsvIR and the MIC was determined via absorption measurements. The P.
aeruginosa strain used in this experiment was a clinical isolate, resistant to multiple antibiotics, obtained from a blood stream infection. Figure 23 shows data indicating that TM ft is 1-2 orders of magnitude more effective at killing pseudomonas than free radezolid. For example, a 0.5 uM concentration of TMR causes a 95% reduction in P. aeruginosa growth, whereas free radezolid had no efficacy up to a 10 WA concentration. Thus '[MR is able to improve the efficacy of radezolid, presumably by enhancing its transport into GNI3.
Claims (35)
1. A compound having the formula:
or a salt thereof, wherein, R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
A is O or S at each occurrence provided A must be S at least once or all of A
are S;
A' is O or S;
E is a linking group; and G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group.
or a salt thereof, wherein, R1, R2, R3, and R4, are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R1, R2, R3, and R4 are optionally substituted with one or more, the same or different, R5;
R5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, thylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
A is O or S at each occurrence provided A must be S at least once or all of A
are S;
A' is O or S;
E is a linking group; and G is a radionuclide, fluorescent molecule, an antibiotic, or an azide group.
2. The compound according to claim 1, wherein E is:
wherein the symbol ~ represents the point of attachement to A' and G;
n' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'1, R"1, R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X1, X2 and Y are at each occurrence individually and independently -O-, -S-, -S-S-, -NH-, -(C=O)-,-NH(C=O)-, (C=O)NH- -O(C=O)-, -(C=O)O-, -S(C=O)-, -(C=O)S-, -SO-, -SO2, - NHSO2-, -SO2NH-,-(CH2CH2O)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be 1 to 22;2.
wherein the symbol ~ represents the point of attachement to A' and G;
n' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14;
m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23;
R'1, R"1, R'2 and R"2 are at each occurrence individually and independently hydrogen, halogen, alkyl, alkoxy, or hydroxyl;
X1, X2 and Y are at each occurrence individually and independently -O-, -S-, -S-S-, -NH-, -(C=O)-,-NH(C=O)-, (C=O)NH- -O(C=O)-, -(C=O)O-, -S(C=O)-, -(C=O)S-, -SO-, -SO2, - NHSO2-, -SO2NH-,-(CH2CH2O)q-,-(CH2)r-, a disubstituted carbocyclyl, a di-substituted aryl, a disubstituted heterocyclyl, or absent;
q can be 1 to 1000; and r can be 1 to 22;2.
3. The compound according to claim 1 or claim 2, wherein A' is O.
4. The compound according to any of claims 2-3, wherein X1 is in each case absent.
5. The compound according to any of claims 2-3, wherein X2 is a hetrocyclic ring.
6. The compound according to any of claims 2-5, wherein X2 is a triazole ring.
7. The compound according to any of claims 1-6, wherein R2, R3, and R4 are in each case hydrogen.
8. The compound according to any of claims 1-7, wherein R1 is independently selected from H, OH, or F.
9. The compound according to any of claims 1-8, wherein G is selected from -(CH2)x18F, wherein x can be 1, 2, 3, 4, 5, 6, 7 or 8, wherein the symbol ~ represents the point of attachement to E;
U is N or CR11;
W is N or CR9;
Z is a carbocyclic or heterocyclic ring;
R7 is alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or more, the same or different R13; or R7 and R11 form a heterocarbocyclic ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R9 is a hydrogen or halogen;
R10 is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen;
R12 is hydrogen;
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulflnyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R19 is hydrogen, alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or more, the same or different R13;
R14, R15, R16, and R17 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R14, R15, R16, and R17 are optionally substituted with one or more, the same or different, R20;
R18 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13; and R20 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
U is N or CR11;
W is N or CR9;
Z is a carbocyclic or heterocyclic ring;
R7 is alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or more, the same or different R13; or R7 and R11 form a heterocarbocyclic ring optionally substituted with R13;
R8 is hydrogen, alkyl or alkanoyl;
R9 is a hydrogen or halogen;
R10 is hydrogen, alkoxy, amino, or alkyl;
R11 is hydrogen, alkoxy, or halogen;
R12 is hydrogen;
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulflnyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R19 is hydrogen, alkyl, carbocyclyl, or aryl, wherein R7 is optionally substituted with one or more, the same or different R13;
R14, R15, R16, and R17 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R14, R15, R16, and R17 are optionally substituted with one or more, the same or different, R20;
R18 is acetylamino, hydrogen, alkyl, halogen, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more, the same or different, R13; and R20 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
10. The compound according to claim 9, wherein Z is:
wherein the symbol ~ represents the point of attachement to E or or the quinolone fragment and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
wherein the symbol ~ represents the point of attachement to E or or the quinolone fragment and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
11. The compound according to claim 10, wherein R13 is independently selected from hydrogen, methyl, or ethyl.
12. The compound according to any of claims 2-11, wherein X1 is in each case absent, R', R", R'1, R"1, R'2, R"2 are in each case hydrogen and X2 is heterocycle.
13. The compound according to any of claims 1-12, wherein X2 is:
14. The compound according to any of claims 2-12, wherein Y is absent.
15. The compound according to any of claims 2-14, wherein n' is 1, 2, 3, or 4.
16. A composition comprising a thiomaltose-based analog of the following formula:
wherein, A is O, NH, S or a direct bond to R8;
R1, R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen, hydroxy, halogen, alkyl, alkoxy, tracer, or 18F;
R8 is E-G, wherein E is a linking group; and G is a tracer, a drug, an antibiotic, an azide group, or other molecule of interest.
wherein, A is O, NH, S or a direct bond to R8;
R1, R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen, hydroxy, halogen, alkyl, alkoxy, tracer, or 18F;
R8 is E-G, wherein E is a linking group; and G is a tracer, a drug, an antibiotic, an azide group, or other molecule of interest.
17. The composition of claim 16 wherein, E is triazole positioned between linking groups such as the following groups alone or in combination, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.
18. A composition comprising a tracer molecule conjugated to a thiomaltose-based analog.
19. The composition of claim 18, wherein the tracer molecule is a positron-emitting radionuclide.
20. The composition of claim 19, wherein the positron-emitting radionuclide is selected from carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82, and strontium-82.
21. The composition of claim 20, wherein the tracer molecule is fluorescent molecule.
22. The composition of claim 21, wherein the fluorescent molecule is a fluorescent dye.
23. The composition of any of claims 16-22, wherein the thiomaltose-based analog is greater than 2, 3, 4, 5 or 6 sugar oligomers.
24. The composition of claim 23, wherein the thiomaltose-based analog comprises glucose oligomers.
25. The composition of claim 24, wherein the glucose oligomers are linked by an .alpha.(1.fwdarw.4) glycosidic bond comprising thiol group.
26. A composition comprising an antibiotic conjugated to a thiomaltose-based analog.
27. The composition of claim 26, wherein the thiomaltose-based analog is greater than 2, 3, 4, 5 or 6 sugar oligomers.
28. The composition of claim 27, wherein the thiomaltose-based analog comprises glucose oligomers.
29. A method of transferring a molecule of interest into bacteria comprising mixing bacteria with a non-naturally occurring conjugate under conditions such that the conjugate is transported across the bacterial cell wall wherein the conjugate comprises a thiomaltose-based analog and a molecule of interest.
30. The method of claim 29, wherein the conjugate is the compound of any of claims 1-15.
31. An imaging method comprising a) administering a tracer molecule conjugated to a thiomaltose-based analog as in any of claims 16-28 to a subject; and b) scanning the subject for a physical property of the tracer molecule.
32. The imaging method of claim 31, further comprising the step of detecting the physical property of the tracer molecule and creating an image highlighting the location of the tracer molecule in the subject.
33. A method of treating or preventing a bacterial infection comprising administering an effective amount of an isolated conjugate to a subject in need thereof wherein the isolated conjugate comprises an antibiotic and an thiomaltose-based analog as in any of claims 16-28.
34. A compound having the following formula:
or derivative thereof wherein, A is O, NH, S or a direct bond to R8;
R1, R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen, hydroxy, halogen, alkyl, alkoxy, tracer, or 18F;
R8 is E-G, wherein E is a linking goup; G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest; or R8 is a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R9;
R9 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
or derivative thereof wherein, A is O, NH, S or a direct bond to R8;
R1, R2, R3, R4, R5, R6, and R7 are, the same or different, hydrogen, hydroxy, halogen, alkyl, alkoxy, tracer, or 18F;
R8 is E-G, wherein E is a linking goup; G is an tracer, a drug, an antibiotic, an azide group, or other molecule of interest; or R8 is a protecting group, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R9;
R9 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, Nmethylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-Nethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
35. The composition of Claim 34 wherein, E is triazole positioned between linking groups such as the following groups alone or in combination, ether, amine, amide, ester, carbonyl, thiol, dithiol, thiolester, aromatic, heteroaromatic, or hydrocarbon groups.
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US4130709A (en) * | 1977-12-08 | 1978-12-19 | Eli Lilly And Company | Pleuromutilin glycoside derivatives |
CA2497881A1 (en) * | 2002-09-12 | 2004-03-25 | The University Of British Columbia | Engineered enzymes and their use for synthesis of thioglycosides |
RU2378282C1 (en) * | 2008-07-30 | 2010-01-10 | Петербургский ин-т ядерной физики им. Б.П. Константинова РАН | Substrates of oligasaccharide class for detecting endo-glycosidehydrolase in presence of exo-acting ferments |
EP4324483A3 (en) * | 2011-01-14 | 2024-05-01 | Emory University | Oligosaccharide conjugates for targeting bacteria and uses related thereto |
-
2015
- 2015-09-21 WO PCT/US2015/051262 patent/WO2016044846A1/en active Application Filing
- 2015-09-21 CA CA2961672A patent/CA2961672A1/en not_active Abandoned
- 2015-09-21 US US15/512,696 patent/US20170274087A1/en not_active Abandoned
- 2015-09-21 EP EP15841531.5A patent/EP3193946A4/en not_active Withdrawn
Also Published As
Publication number | Publication date |
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WO2016044846A1 (en) | 2016-03-24 |
US20170274087A1 (en) | 2017-09-28 |
EP3193946A4 (en) | 2018-05-23 |
EP3193946A1 (en) | 2017-07-26 |
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